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0022-5347/97/1586-2069$03.00/0 JOURNAL OF UROLOGY Vol. 158,2069-2073, December 1997 Copyright Q 1997 by AMERICANUROLOGICAL ASS~CIATION, INC. Printed in U.S.A. - CITRATE IS AN EFFECTIVE PROPHYLAXIS AGAINST RECURRENT OXALATE NEPHROLITHIASIS

BRUCE ETTINGER,* CHARLES Y. C. PAK, JOHN T. CITRON, CARL THOMAS, BEVERLEY ADAMS-HIJET AND ARLINE VANGESSEL From the Diuision of Research, Kaiser Permanente Medical Care Program, Oakland, California, the Department of Metabolism, Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, Department of Medicine, Kaiser Permanente Medical Center, Walnut Creek, California, Department of Urology, Kaiser Permanente Medical Center, San Francisco, California, and Kaiser Foundation Research Institute, Kaiser Foundation Hospitals, Oakland, California

ABSTRACT Purpose: We examined the efficacy of potassium- in preventing recurrent calcium oxalate kidney calculi. Materials and Methods: We conducted a prospective double-blind study of 64 patients who were randomly assigned to receive placebo or potassium-magnesium citrate (42 mEq. potassium, 21 mEq. magnesium, and 63 mEq. citrate) daily for up to 3 years. Results. New calculi formed in 63.6%of subjects receiving placebo and in 12.9%of subjects receiving potassium-magnesiumcitrate. When compared with placebo, the relative risk of treat- ment failure for potassium-magnesium citrate was 0.16 (95%confidence interval 0.05 to 0.46). potassium-magnesium citrate had a statistically significant effect (relative risk 0.10,95%confi- dence interval 0.03 to 0.36) even after adjustment for possible confounders, including age, pretreatment calculous event rate and urinary biochemical abnormalities. Conclusions: Potassium-magnesium citrate effectively prevents recurrent calcium oxalate stones, and this treatment given for up to 3 years reduces risk of recurrence by 85%. KEYWORDS: calcium oxalate, citrates, kidney calculi, magnesium, potassium effectively reduces recurrence of calcium vestigators at the University of Texas Southwestern Medical oxalate nephrolithiasis.' The salutary effect of citrate is at- Center at Dallas, Texas.l2 Compared with placebo, short- tributed to its ability to form a soluble complex with urinary term (1-week)treatment using potassium-magnesium citrate calcium and to correct excess urinary acidity.* Additionally, combined with constant dietary regimen increased urinary citrate enriched urine has been shown experimentally to citrate levels by 611, urinary magnesium levels by 43%, and have reduced tendency for nucleation, growth, and agglom- urinary pH by 0.6 unit.13 UMary saturation of calcium ox- eration of calcium oxalate crystals.*%3However, potassium alate decreased by 31%, inhibition of calcium oxalate crys- citrate shares with other potassium the tendency to tallization increased by 46%, and inhibition of calcium phos- irritate gastric mucosa, and this problem can limit patient phate crystallization increased by 90%. These effects were acceptability. In clinical trials of potassium citrate, incidence more prominent than those achieved using potassium citrate of gastrointestinal adverse events ranged from 9 to 17%.1-4 of equivalent potassium c0ntent.1~ Dietary has been suggested to cause We hypothesized that long-term use of this formulation increased risk of calcium calculi,6 and magnesium supple- might combine the beneficial urinary physicochemical effects mentation has been recommended as prophylaxis.6 By en- of citrate and magnesium, thereby reducing the risk of kid- riching urine with magnesium, the rate of calcium oxalate ney stone formation. Containing less than the usual amount Crystal growth in vitro can be slowed.7 However, clinical of potassium, this citrate could reduce incidence of gas- trials of magnesium supplementation did not consistently trointestinal side effects. Therefore, we tested tolerability show therapeutic effects,8-10 probably because supplementa- and effectivenessof potassium-magnesium citrate in patients tion fails to produce sufficiently high urinary magnesium diagnosed as having recurrent, active calcium oxalate neph- concentration. Isotope studies have indicated poor intestinal rolithiasis. absorption of magnesium sdts.11 In a clinical trial using magnesium , only 4% of administered magnesium was excreted in urine within 24 hours.10 High dosages of METHODS magnesium salts are impractical because they cause diar- Subjects. From among calculus analyses done at Kaiser rhea. Permanente Medical Centers in Northern California, we se- Recently a new formulation of citrate containing potassium lected all reports of calculi containing at least 50% or more and magnesium at a lower (4:l) ratio was developed by in- calcium oxalate. After reviewing the medical records, we selected patients who had active, recurrent calculous disease Accepted for publication June 20, 1997. uests for reprints: Division of Research, Kaiser PeFanente and no secondary cause for nephrolithiasis. All subjects had M*edica"4 Care Program, 3505 Broadway, Oakland, Califorrua 94611- had 2 or more calculi within the previous 5 years and at least 5714. 1 calculus within the previous 2 years. Excluded were sub- Supported by United States Public Health Service Research who had obstructive uropathy, chronic urosepsis, renal Grants Pol-DK20543 jects and FD-R-000636. failure (serum creatinine greater than 1.8 mgJdl., normal 1.5 Editor's Note: This article is the third of 5 published in this or less), renal tubular acidosis, or lithotripsy treatment hue for which category 1 CME c-ts cap be earnd. In- hctions for obtained dtaare gwen anth the queshons within the previous 6 months. Patients were advised of the On Pages 2274 and 2275. study design and gave informed consent as specified by the 2069 2070 POTASSIUM-MAGNESIUM CITRATE PREVENTS NEPHROLITHIASIS Northern California Kaiser Permanente Institutional Re- at baseline and at each followup visit by using a Likert score view Board. (I-none, 2-slight, 3-some, 4-considerable). We deter- Outcomes. Study participants were given simple metabolic mined that subjects had a study related gastrointestinal assessment while following an unrestricted diet. Automated symptom if the symptom score was greater at any followup chemistry panels (SMA-24) and 24-hour urine collections visit than it was at the start of the study and if it had a value were obtained at the beginning of the study to determine of at least 3 on the Likert scale. At each visit subjects were baseline values, at 5 months, and every 4 months thereafter also asked if they found the study medication disagreeable. for as long as 37 months. We measured urine for total vol- These analyses included subjects who left the study because ume, creatinine level, pH, potassium, calcium, magnesium, of adverse effects. , phosphate, chloride, sulfate, ammonium, oxalate Statistical analysis. Descriptive statistics were computed and citrate. Results of these tests were used to calculate for baseline variables in each group. For adverse events we urinary saturation of stone forming substances (calcium ox- used Fisher's exact test to compare differences in proportions alate, sodium urate, brushite LCaHPO, * 2waterl) and the between the 2 groups. amount of undissociated uric .14 Urine could not be ana- Repeated measures analysis of variance models were used lyzed for inhibition of either calcium oxalate crystallization to assess urinary biochemical parameters. A statistically sig- or calcium phosphate crystallization13 because the fresh nificant interaction between group and time factors indicated urine samples required could not be shipped to the Univer- intergroup differences in treatment response. Results were sity of Texas Southwestern Medical Center for Mineral Me- tabulated using baseline and mean followup values and were tabolism and Clinical Research in Dallas, where the analysis compared within each treatment group using paired t tests. was done, quickly enough hmSan Francisco. On the basis of Statistical significance levels as reported were not adjusted %hour urinary excretion, we defined low urine volume as for multiple testing. 1200 ml. or greater excreted, hypercalciuria as 300 mg. or Cox proportional hazards models were used to estimate greater calcium excreted for men and 250 mg. or greater for relative risk (potassium-magnesium citrate versus placebo) women, hyperuricosuria as 800 mg. or greater ex- of having a calculous event. Covariates assessed in the model creted for men and 750 mg. or greater for women, hyperox- included gender, age, rate of calculus formation within 3 aluria as 40 mg. or greater oxalic acid excreted and hypoci- years before the study, baseline calculus burden and pres- traturia as 320 mg. or greater citrate excreted. ence of urinary biochemical abnormalities. A similar analysis Pretreatment rates of calculus formation were based on all was done by adding as treatment failures the 6 patients (5 calculous events that occurred within 3 years before the who received potassium-magnesium citrate, 1 who received study. For each subject we obtained a coned view x-ray film placebo) who did not have a stone event but who left the of the kidneys at the start of the study and annually there- study after having an adverse reaction to the study drug. after. We calculated an index of obesity, body mass index, by Statistical significance level was a = 0.05. Statistical anal- dividing each subject's weight (kg.) by the square of the ysis was done using computer statistical software. height (m.). To determine biochemical effects of treatment, we calculated for each subject the mean of all values for all RESULTS treatment visits for each variable and the percentage Baseline clinical variables were similar for potassium- changes from baseline values. For each group (potassium- magnesium citrate and placebo groups (table 1). Mean uri- magnesium citrate or placebo) we calculated mean baseline, nary biochemical parameters as well as prevalence of defined treatment and percentage change values for each biochemi- biochemical parameters and prevalence of defined biochem- cal variable. ical abnormalities also did not differ significantly between Based on previous experience which showed that the start the 2 groups. Prevalence of multiple urinary metabolic de- of effective therapy may be marked by washout of small rangements was similar between groups. Among subjects calculi or gravel, we included in the study design a 1-month who received placebo 84.8% had 1 or more, 51.5% had 2 or grace period. During this time, any passage of calculi was not considered to indicate failure of therapy and did not cause removal of any subject from the study. Thereafter any pas- sage of new calculi, radiographic appearance of new calculi, TABLE1. Baseline clinical characteristics of nephrotithzasis studv mOUD or enlargement of preexisting calculi seen radiographically ~ was considered to indicate treatment failure and caused the Placebo Potassium-Magnesium patient to be removed from the study. An impartial referee Citrate identified calculous events by judging clinical information No. pts. 33 31 and x-ray films without knowing treatment status. avoid Age (yrs.) 47.45 t 9.05 48.6 I11.22 To Menomen 2W5 22J9 further bias the referee compared x-ray films without know- Baseline No. calculi/pt. 1.70 t 1.91 1.68 5 1.92 ing the temporal sequence. 9% pts. with calculi (No.) 72.7 (24) 71.0 (22) Treatment assignment. Because previous researchers re- No. calcuWpt. in last 3 yrs. 1.7 2 0.8 1.7 5 0.8 ported correlation between calculus burden and risk of recur- Urinary: PH 5.96 t 0.41 6.01 t 0.46 rent formation of calculi,11 we stratified study subjects on the Total vol., (1Jday) 1.74 t 0.70 1.98 t 1.15 basis of calculus absence or presence. Within each stratum, Calcium (mg./day) 275 t 131 237 f 120 using computer-generated random numbers, we randomly mgJday 1051 2 299 983 5 329 assigned subjects to receive visually identical tablets of ei- Oxalate mglday 36 _f 12 37 f 13 Sodium mEqJday 172 2 87 164 5 66 ther placebo or potassium-magnesium citrate. All subjects Potassium mEqJday 58 5 20 56 5 25 were instructed in a diet that recommended restricting salt, Magnesium mgJday 121 t_ 47 116 t 44 refined sugar, foods rich in oxalate and animal protein but Ammonium mEqlday 42 t 19 38 I10 allowed up to 2 servings of dairy foods per day. Subjects were Citrate mgJday 549 t 280 587 2 374 Uric acid mglday 695 2 227 722 f 229 further instructed to take 2 tablets of the study drug 3 times Activity product: daily. This provided a daily dose of 42 mEq. potassium, 21 Calcium oxdate m.2 x lo-* 1.77 2 0.87 1.40 2 0.76 mEq. magnesium, and 63 mEq. citrate to subjects who re- Brushite m.* x 5.54 2 4.68 4.10 -t 5.43 ceived active drug. Compliance with medication regimen was Sodium urate m.' x lo-+ 1.28 t 0.85 0.99 -t 0.65 confirmed by counting tablets regularly, but compliance with Undissociated uric acid mg./day 152 t 101 162 f 111 Data presented as mean 2 SD. dietary instruction was neither encouraged nor assessed. No statistically significant differences between placebo and potassium- Adverse events. Gastrointestinal symptoms were assessed magnesium citrate groups. POTASSIUM-MAGNESIUM CITRATE PREVENTS NEPHROLITHIASIS 207 1 more and 24.2% had 3 or more abnormalities, whereas among subjects receiving potassium-magnesium citrate, 73.3%had 1 or more, 40.0% had 2 or more and 16.7% had 3 or more abnormalities or greater. FiWn subjects left the potassium-magnesium citrate arm --,-, ofthe study, and 8 subjects left the placebo arm. About half "Ia ofthese subjects left the study during its first 6 months. The c 0 0.6 1 =st left throughout the remaining period. Adverse reactions 3j ascribed to study medication accounted for 5 (16.1%) subjects who stopped taking potassium-magnesium citrate (3 stopped because of gas, bloating or nausea, 1 stopped because of difficulty swallowing the tablet, 1 stopped because of skin n rash). Difficulty swallowing tablets caused 1 (3.0%)to stop Relalive risk (KMgCitrate/Placebo) - 0.16 taking placebo. We saw no statistically significant differences 95% Conlldence Interval (0.05 to 0 46) in individual gastrointestinal symptoms between the placebo and active drug groups. About 11% of all subjects had diffi- culty swallowing the rather large pills. During the study 0.0 39.4% of the placebo group and 41.9% of the potassium- 0 4 8 12 16 20 24 28 32 36 magnesium citrate group had new or worsening baseline Time (months) symptoms of eructation, bloating or gaseousness. However, Proportion of patients remaining free of stones during treatment only 15.2% of the placebo group and 25.8% of the potassium- wit2t.assium-magnesium citrate (Mllg Citrate) or placebo. Unad- magnesium citrate group reported more than slight symp- jus relative risk is shown. toms. was not reported by placebo users but was reported by 11.5% of potassium-magnesium citrate users. However, only 1 subject (3.9%) noted this problem at more than followup visit. Overall of patients using group and in 12.9% of the potassium-magnesium citrate 1 21.4% group (see figure). These calculous events consisted mainly of potassium-magnesium citrate and 3.58% of subjects taking placebo found the study drug more than slightly disagreeable new stones seen on x-ray films or passed. Such events ac- counted for of treatment failures in the placebo group 88 reported at more than followup visit or left the study 75% 1 and 81% of treatment failures in the potassium-magnesium because of it (p = 0.052). Compliance with study drug protocol was excellent in both citrate group. Of the 8 stones passed, 6 were analyzed and all contained predominantly calcium oxalate. Compared with groups. Median compliance was 86.9% for placebo and 89.0% for potassium-magnesium citrate. More than compli- placebo, risk of treatment failure using potassium- 70% magnesium citrate was confidence interval 0.05 ance was achieved by of patients receiving placebo and 0.16 (95% to 73.1% 0.46). Adjustment for possible confounders including age, 80.8% of those receiving potassium-magnesium citrate. pretreatment calculous event rate, low urine volume and Table shows the effect of treatment on urinary biochem- 2 hyperoxaluria also indicated a substantially reduced risk of &try and on saturation of calculus forming salts. In the failure (relative risk confidence interval to placebo group, no statistically significant change seen in 0.10, 95% 0.03 was 0.36).Adding as treatment failures the 6 subjects who left my urinary biochemical or saturation parameter. In the the study because of adverse drug events still demonstrated potassium-magnesium citrate group, statistically significant efficacy of potassium-magnesium citrate compared with pla- hcreases occurred in urinary magnesium, potassium and cebo, given that the intent to treat analysis yielded a relative citrate levels. Marginal increase in urinary pH (p = 0.08) and risk of confidence interval to statistically significant decline in urinary ammonium levels 0.35 (95% 0.16 0.76). were seen, as was a modest statistically significant increase urinary oxalate levels. We found no statistically signifi- DISCUSSION 9tchange in urinary saturation of calcium oxalate, brush- We have found that treatment using potassium- ?t" or monosodium urate (as assessed by activity product) or magnesium citrate markedly reduces risk of recurrent cal- 1l1 uric acid (as assessed by daily excretion rate of undissoci- cium oxalate nephrolithiasis. In most clinical trials of kidney ated uric acid). stone prophylaxis, subjects receiving placebo have a 15 to New calculous events occurred in 63.6% of the placebo 20% annual rate of stone recurrence,1o a rate somewhat

TABLE2. Urinary biochemistry and saturation after treatment using potassium-magnesium citrate for recurrent rrephrolithiasis Placebo Gmup Potassium-Magnesium Citrate Group Pretreatment Posttreatment % Change Pretreatment Posttreatment 5 Change

Magnesium mgJday 121 :47 105 ? 32 5.7 I51.9 116 c 44 142 C 42' 29.9 I42.8 Potassium mEqJday 58 2 20 58: 17 10.6 2 36.9 56 :25 89 ? 27t 69.1 z 49.1 Citrate mgJday 549 f 280 548 ? 265 11.1 I62.5 587 2 37.4 769 c 289* 50.4 5 73.7 PH 5.96 -+ 0.41 6.02 2 0.32 0.6 2 8.7 6.01 :0.46 6.29 2 0.58 4.5 2 10.4 brnonium mEqJday 41 2 19 37 2 16 -1.5 I44.1 38 ? 10 28 C lot -21.5 f 28.0 Calcium mgJday 275 2 131 261 I123 9.3 z 38.2 237 z 120 225 f 92 0.5 z 36.2 &alate mgJday 36 Z 12 39Z 10 15.1 Z 36.4 37 5 13 44 2 21' 18.7 2 28.1 Phosphorus mglday 1051 f 299 1014 2 325 0.4 f 21.1 983 f 329 995 r 340 6.4 f 20.5 uric acid mgJday 695 2 227 694 2 194 2.0 c 23.5 722 z 229 726 z 210 2.3 z 19.7 Total vol. IJday 1.74 Z 0.70 1.79 ? 0.84 -0.6 ? 29.2 1.98 Z 1.15 2.01 f 1.00 7.8 I29.2 Activity product: Calcium odate, m,' x 1.77 ? 0.87 1.72 2 0.53 27.6 ? 64.2 1.40 Z 0.76 1.48 f 7.75 7.9 t 49.0 Brushite, m.* x 10-~ 5.54 ? 4.68 4.82 Z 4.02 21.6 2 71.9 4.10 Z 5.43 5.75 z 3.54 106.4 f 146.1 sodium urate, m? x lo-' 1.28 2 0.85 1.32 2 1.05 55.3 c 128.7 9.89 2 6.48 1.24 c 7.44 36.2 z 73.2 - Undhwiated uric acid mgJday 152 Z 101 185 Z 124 80.5 I206.9 162 ? 111 105 ? 136 58.6 f 340.7 Data presented as mean z SD. P 10.05 versus pretreatment. t P <0.001 versue pretreatment. 2072 POTASSIUM-MAGNESIUM CITRATE PREVENTS NEPHROLITHWIS lower than the 27% rate observed in our placebo group. In daily left the study because of magne. trials of active drug therapy ( or potassium sium hydroxide related diarrhea, whereas this condition did citrate) the annual recurrence rate is about 5%,1.10 a rate not affect subjects taking 650 mg. of magnesium hydroxide similar to that observed for patients treated with potassium- daily.10 In that study, 24-hour urinary excretion of magne- magnesium citrate in our study. This new drug formulation sium increased 50 mg. when 1,500 mg. per day given, but this thus appears to have therapeutic efficacy similar to or better treatment was no more effective than placebo in reducing than the calculus prophylaxes usually prescribed. recurrence of calculi. In the current study potassium. Previous studies of citrate have focused on hypocitraturia magnesium citrate did not cause frequent or troublesome and have recommended citrate treatment on the basis of this diarrhea, but it raised urinary magnesium levels by a mean finding.' Fewer than 20% of patients in our study had hy- of only 26 mg. per day, a smaller increase than we had hoped pocitraturia, and the beneficial effect of citrate on calculus to achieve. The small incremental rise in urinary magnesium recurrence was not limited to this group. Therefore, our re- levels may contribute to the effectiveness of potassium- sults support unselective use of citrate for preventing cal- magnesium citrate in preventing calculus formation but is cium oxalate lithiasis. unlikely to be solely responsible for this effectiveness. Obtaining patient acceptance of long-term drug prophy- Our study had several limitations. The number of subjects laxis is a challenge for all clinicians who attempt to manage was too small to allow definitive assessment of drug effec- calculous disease medically. Nearly half of subjects given tiveness for each type of urinary metabolic abnormality. Sim- potassium-magnesium citrate, an effective prophylaxis, did ilarly our study observed too few treatment failures for us to not take the drug continuously for 3 years. Compliance and analyze reasons for failure. We did not test potassium- continuation obtained from highly motivated research sub- magnesium citrate against potassium citrate, so we cannot jects who participate in double-blinded studies may not be as provide evidence to show whether the new formulation has good in clinical practice. For any long-term prophylactic reg- better tolerability or effectiveness. A large number of pa- imen, ease of use and freedom from side effects are impor- tients would be required for the study to have sufficient tant. Compared with a small thiazide tablet taken once daily, power to determine whether these similar drugs have clinical potassium-magnesium citrate has the disadvantage of being differences. available only as a large tablet that must be taken 2 at a time 3 times daily. Pill size was a problem for about 1 in 9 study CONCLUSIONS subjects. However, we specifically studied drug tolerability at each clinic visit, and a higher prevalence of specific symp- Potassium-magnesium citrate can substantially reduce the toms can be expected when these symptoms are elicited from 3-year recurrence rate of calcium oxalate stone formation. a checklist than when subjects are asked nonleading queries. This benefit does not depend on the presence of hypocitratu- We therefore believe that our findings that gastrointestinal ria, and the drug can therefore be prescribed for calcium symptoms in the potassium-magnesium citrate and placebo oxalate calculus prophylaxis without extensive metabolic groups did not differ to any statistically significant degree testing. Whether substituting magnesium for potassium in and that only a few subjects leR the study because of gastro- the drug formulation provides additional therapeutic effect is intestinal problems indicate good tolerability of potassium- unclear because the incremental rise in urinary magnesium magnesium citrate, although clinicians should be aware that excretion is small. Gastrointestinal tolerability of potassium- potassium salts can irritate the gastrointestinal tract. magnesium citrate compared with potassium citrate must be Prevention of stone recurrence by potassium-magnesium proved by appropriate comparative studies. citrate could probably be ascribed to loading and to John R. Poindexter, Center for Mineral Metabolism and citraturic and magnesiuric effects of treatment. As described Clinical Research, University of Texas Southwestern Medical in a short-term metabolic study,l3 subjects taking potassium- Center, provided data management and Jan Koska per- magnesium citrate in a randomized trial had a statistically formed laboratory analysis of urine. Mission Pharmacal, San significant or marginal increase in urinary pH, citrate levels Antonio, Texas, supplied the drug study material. and magnesium levels. These effects probably further inhib- ited crystallization of calcium salts,'3 although for technical REFERENCES reasons the inhibitory action could not be measured directly. Compared with results reported in the short-term metabolic 1. Pak, C. Y. C., Fuller, C., Sakhaee, K, Preminger, G. M., Britton, study,13 potassium-magnesium citrate treatment in this trial F. Long-term treatment of calcium nephrolithiasis with potas- sium citrate. J. Urol., 134: 11, 1985. produced a less marked rise in urinary pH (0.3 unit versus 2. Pak, C. Y. C. Citrate and renal calculi. Miner Metab., 0.6), in citrate levels (182 versus 389 mg. per day), and in 13 257, 1987. magnesium levels (26 versus 42 mg. per day). This attenu- 3. Kok, D. J., Papapoulos, S. E., Bijvoet, 0. L. M. Excessive crystal ated effect probably results from a lower dose (63 versus 74 agglomeration with low citrate excretion in recurrent stone- mEq. citrate per day) and from a lower compliance rate (87 to formers. Lancet, 1: 1056, 1986. 89%versus 100%).Moreover, whereas urinary oxalate levels 4. Zerwekh, J. E., Reed, B. Y., Heller, H. J., Gonzalez, G. B., did not change significantly during the short-term metabolic Haussler, M. R. and Pak, C. Y. C. Normal vitamin D receptor study,l3 they increased modestly in this trial, probably be- concentration and responsiveness to 1,25-dihydroxyvitamin cause a random diet was used instead of a constant metabolic D3 in skin fibroblasts from patients with absorptive hypercal- ciuria. Calcif. Tissue Int., in press. diet. Thus, urinary saturation of calcium oxalate, which in an 5. Preminger, G. M., Baker, S., Peterson, R., Poindexter, J. and earlier metabolic study was shown to decline, did not change Pak, C. Y. C. Hypomagnesiuric hypocitraturia: an apparent in this trial. new entity for calcium nephrolithiasis. J. Lithotripsy Stone In our trial, incremental increases in urinary pH and ci- Dis., 1: 22, 1989. trate levels achieved with potassium-magnesium citrate 6. Moore, C. A. and Bunce, G. E. Reduction in frequency of renal were less than those observed when a comparable dose of calculus formation by oral magnesium administration: a pre- potassium citrate was given. In an earlier trial of potassium liminary report. Invest. Urol., 2 7, 1964. citrate administered at a dosage of 60 mEq. per day,' urinary 7. Meyer, J. L. and Smith, L. H. Growth of calcium oxalate crystals. pH rose by about 0.5 unit (compared with a rise of 0.3 unit in I. A model for urinary stone growth. Invest. Urol., 1331, 1975. our trial), and urinary citrate levels increased by about 300 8. Johansson, G., Backman, U.,Danielson, B. G., Fellstrom, B., Ljunghall, S. and Wikstrom, B. Magnesium metabolism in mg. per day (compared with an increase of 182 mg. per day). renal stone formers. Effects of therapy with magnesium hy- The reason for this discrepancy is not apparent. droxide. Scand. J. Urol. Nephrol., 53: 125, 1980. In a previous study 13.3%'of subjects taking 1,500 mg. of 9. Wilson, D. R., Straws, A. L. and Manuel, M. A. Comparison of POTASSIUM-MAGNESIUM CITRATE PREVENTS NEPHROLITHlASIS 2073 medical treatments for the prevention of recurrent calcium ment. This well performed, randomized, prospective trial investi- nephrolithiasis [abstract]. Urol. Res., 1239, 1984. gates the nonselective use of a new medimtion. potaasium- 10. Ettinger, B., Citron, J. T., Livermore, B. and Dolman, L. I. magnesium citrate, to prevent recurrent stone formation. In a Chlorthalidone reduces calcium oxalate calculous recurrence blinded study the authors have demonstrated significant reduction but magnesium hydroxide does not. J. Urol., 139: 679, 1988. in stone eventa in the pupreceiving active medication, over those 11. Graham, L. A., Caesar, J. J. and Burgen, A. S. V. Gastrointes- patients who were given the placebo. While the authors acknowledge tinal absorption and excretion of Mg8 in man. Metabolism, 9: some limitations of the new medication, potassium-magnesium ci- 646, 1960. trate appears to have the significant advantage of preventing recur- 12. Koenig. K,Padalino, P., Alexandrides, G. and Pak, C. Y. C. rent stones in a noneelective group of calcium stone formers. More- Bioavailability of potassium and magnesium, and citraturic over, the medication was relatively well tolerated and a metabolic response from potassium-magnesium citrate. J. Urol., 14& evaluation was not required in order to gain the beneficial effects of 330, 1991. this new preparation. 13. Pak, C. Y. C., Koenig, K, Khan, R., Haynes, S. and Padalino. P. This study poses interesting questions for those of us who have Physicochemical action of potassium-magnesium citrate in long supported the use of selective medical therapy to prevent recur- nephrolithiasis. J. Bone Miner Res., ?: 281, 1992. rent nephmlithiasis. While trained in the 'Dallas School" of stone 14. Pak, C. Y. C., Skurla, C. and Harvey, J. Graphic display of disease, 1 have long believed in the concept of selective medical urinary risk factors for renal stone formation. J. Urol., 154: management to correct specific underlying physiuxhemical and 867, 1985. physiological defecta responsible for recurrent stone disease. Yet, these data suggest that similar success rates in inhibiting new stone EDITORIAL COMMENT disease can be achieved with nonselective administration of potassium-magnesium citrate. In addition, other investigators are Important advances during the last 25 years have significantly looking at alternative approaches to the medical management of changed the surgical and medical management of stone disease. nephrolithiasis, which may also reduce the need for comprehensive While shock wave lithotripsy and endourological techniques have metabolic evaluation and extensive medical followup. In the ever- basically supplanted the need for open stone removal, debate contin- changing medical environment, economics may eventually dictate ues as to the most appropriate metabolic evaluation and the need for that nonselective treatment of certain disorders, especially stone medical management to prevent recurrent nephrolithiasis. Previous disease, may provide a cost-effective alternative to the more classic studies have demonstrated that medical therapy can significantly "physiologically based" treatments of the past. reduce recurrent stone disease, and suggest that medical prevention It only with well performed randomized, prospective trials such may be more cost-effective than repeat noninvasive stone removal is as the current investigation that we will ultimately be able to deter- procedures. Yet, many physicians continue to avoid medical prophy- mine the most effective, safe and cost efficient approach to prevent laxis of stone disease due to complexity of the metabolic evaluation recurrent stones. Additional long-term clinical trials are warranted as well as limited access to various diagnostic tests. Moreover, some to achieve this goal. have criticized the validity of previous studies that have demon- strated beneficial effects of medical management of stone disease, Glenn M. Preminger due to the lack of randomized prospective trials. Division of Urvlqw The authors have provided exciting new information that ad- Duke University Medical Center dresses many of the problems surrounding medical stone manage Durham,North Carolina