Kidney International, Vol. 57 (2000), pp. 607–612

Potassium-magnesium citrate versus potassium chloride in thiazide-induced hypokalemia

LISA-ANN WUERMSER,CHRISTOPHER REILLY,JOHN R. POINDEXTER,KHASHAYAR SAKHAEE, and CHARLES Y.C. PAK

Center for Mineral Metabolism and Clinical Research, University of Texas, Southwestern Medical Center, Dallas, Texas, USA

Potassium-magnesium citrate versus potassium chloride in uretic therapy is hypokalemia, which is reported to occur thiazide-induced hypokalemia. in about half of the patients on chronic thiazide treat- Background. The purpose of this study was to compare the ment [2]. Although less well appreciated, thiazide may value of potassium-magnesium citrate (KMgCit) with potas- sium chloride in overcoming thiazide-induced hypokalemia. also provoke renal magnesium loss [3] and hypocitraturia Methods. Sixty normal subjects first took hydrochlorothia- [4]. The resulting magnesium depletion may exaggerate zide (HCTZ; 50 mg/day). After three weeks of treatment (or neuromuscular and cardiac side-effects of hypokalemia, earlier if hypokalemia developed), they were randomized to including muscle weakness, paralysis, and arrhythmia take KMgCit (42 mEq K, 21 mEq Mg, and 63 mEq citrate/ [5]. Magnesium depletion may also blunt the ability of day) or potassium chloride (42 mEq/day) for three weeks while continuing on HCTZ. potassium chloride to correct hypokalemia [6]. In the man- Results. KMgCit significantly increased the serum potassium agement of stone disease, the beneficial hypocalciuric ac- concentration from 3.42 Ϯ 0.30 mEq/L on HCTZ alone to tion of thiazide may be opposed by the reduction in uri- about 3.8 mEq/L (P Ͻ 0.001). Potassium chloride produced a nary citrate, an inhibitor of stone formation [7]. similar increase in serum potassium concentration from 3.45 Ϯ 0.44 mEq/L to about 3.8 mEq/L (P Ͻ 0.001). KMgCit signifi- It is customary to treat hypokalemia of thiazide ther- cantly increased the serum magnesium concentration by 0.11 to apy with potassium chloride supplementation. Unfortu- 0.12 mEq/L (P Ͻ 0.01), whereas potassium chloride produced a nately, potassium chloride does not prevent or correct marginal decline or no significant change. KMgCit was less magnesium depletion. Moreover, potassium chloride it- effective than potassium chloride in correcting HCTZ-induced self has no effect on urinary citrate excretion [8] and hypochloridemia and hyperbicarbonatemia. KMgCit, but not potassium chloride, significantly increased urinary pH (by only modestly increases urinary citrate in the setting of about 0.6 unit), citrate (by about 260 mg/day), and urinary hypokalemia [4]. magnesium. Recent studies suggest that potassium-magnesium ci- Conclusions. KMgCit is equally effective as potassium chlo- trate (KMgCit), formulated for the prevention of cal- ride in correcting thiazide-induced hypokalemia. In addition, cium-containing renal stones [9, 10], may be advanta- KMgCit, but not potassium chloride, produces a small but significant increase in serum magnesium concentration by de- geous over potassium chloride as an adjunctive agent to livering a magnesium load, and it confers alkalinizing and citra- be used with thiazide. In normal subjects undergoing a turic actions. short-term thiazide treatment, the coadministration of KMgCit has been shown to ameliorate hypokalemia and to produce a small but significant increase in the serum Thiazide is widely used for the control of essential magnesium concentration [11–13]. Moreover, it substan- hypertension and fluid retention. Thiazide is also fre- tially increased urinary citrate by providing an alkali quently employed in the treatment of hypercalciuric load. However, these studies compared KMgCit with nephrolithiasis, because it can correct hypercalciuria by potassium citrate or magnesium citrate, but not with the enhancing renal tubular reabsorption of calcium [1]. A standard of care, potassium chloride. frequent and potentially serious complication of this di- We therefore sought to compare the efficacy of KMgCit with potassium chloride in treating thiazide- Key words: hypercalciuric nephrolithiasis, diuretic therapy, hypoka- induced hypokalemia. We found that KMgCit is equally lemia, hypomagnesemia. effective as potassium chloride in correcting thiazide- Received for publication March 23, 1999 induced hypokalemia, and unlike potassium chloride, and in revised form August 30, 1999 KMgCit enhances urinary citrate excretion and produces Accepted for publication September 9, 1999 a small but significant increase in the serum magnesium  2000 by the International Society of Nephrology concentration.

607 608 Wuermser et al: KMgCit versus potassium chloride in hypokalemia

METHODS cal in appearance and size, both medications were pre- Clinical data pared as wax matrix formulations by the Mission Phar- macal Company (San Antonio, TX, USA). KMgCit is This study was approved by the Institutional Review an investigational drug (IND 36,276) for which the Uni- Board of the University of Texas Southwestern Medical versity of Texas Southwestern Medical Center is the Center. Normal adult volunteers were recruited for this sponsor, and one of the authors (C.Y.C.P.) is the princi- double-blind randomized trial by fliers and word of pal investigator. None of the investigators own equity mouth. or consult for Mission. Mission has provided partial re- After obtaining informed consent, subjects were search support, as well as a free supply of investigational screened by history, physical examination, serum chemis- drugs. try, complete blood counts, electrocardiogram, occult Subjects were evaluated in an outpatient setting, be- blood in feces, and 24-hour urinary chemistries. Subjects fore thiazide treatment, and weekly thereafter (1 to 3 were excluded from the study if they had hypokalemia weeks of HCTZ alone, 3 weeks of HCTZ plus KMgCit or hyperkalemia, hypomagnesemia, creatinine clearance or potassium chloride). At each visit, a venous blood of less than 0.9 mL/min/kg, anemia, occult blood in feces, sample was drawn before lunch, to correspond to 4.5 or arrhythmia. They did not have history of renal stones, hours after taking HCTZ and the morning dose of other kidney diseases or peptic ulcer disease. They were KMgCit or potassium chloride, for the measurement of not taking any potassium or magnesium supplements or potassium, magnesium, chloride, and bicarbonate. Urine medications that could alter potassium or magnesium was collected in a 24-hour pool for the analysis of pH, metabolism. citrate, and magnesium. Stool was examined for occult blood before (pre-HCTZ) and at the conclusion (3 weeks Experimental design of HCTZ and supplement) of the study by using the The basic experimental design was described pre- Hemoccult test. At each visit, a side-effect questionnaire viously [11–13]. The study was divided into two phases [11–13] was completed that addressed 14 gastrointestinal conducted in sequence. Hydrochlorothiazide (HCTZ) symptoms [11] and four symptoms of hypokalemia or alone was given in phase I (HCTZ phase). In phase II volume depletion [11]. Each side effect was rated from (supplement phase), HCTZ was provided with a potas- one (none) to four (Ͼ7 episodes per week) for frequency sium supplement (KMgCit or potassium chloride). Sub- and one (none) to four (severe) for severity. Thus, the jects were instructed on a diet with a daily composition lowest score was one and the highest was four for each of approximately 45 to 55 mEq potassium, 160 to 200 symptom. mg (13.2 to 16.4 mEq) magnesium, 90 to 120 mEq so- Serum potassium was measured by using an ion-spe- dium, 120 to 150 mEq chloride, and 3 L fluids. The cific electrode and serum magnesium by atomic absorp- adherence to this diet was reinforced at each visit. tion spectrophotometry in the laboratory of the General In phase I, all subjects were placed on HCTZ 50 mg Clinical Research Center. Serum chloride and total car- with breakfast each day. They were evaluated weekly bon dioxide (bicarbonate) were measured as a part of for the measurement of serum potassium. Subjects who multichannel screen with an autoanalyzer. Urinary mag- developed hypokalemia (serum K Ͻ 3.5 mEq/L) during nesium was analyzed by atomic absorption spectropho- the first two weeks of treatment with HCTZ alone imme- tometry and citrate was analyzed by the citrate lyase diately entered phase II. Subjects who completed three method in the Mineral Metabolism Laboratory. weeks of treatment with HCTZ alone entered phase II whether or not they developed hypokalemia. Statistical analysis During phase II, subjects continued to take HCTZ (50 For blood and urinary parameters, repeated-measures mg/day) with breakfast for three more weeks. They were analysis of variance with a grouping factor for the two randomized between KMgCit and potassium chloride treatment groups and a repeated factor for five measure- groups, stratified according to gender. Subjects in ments (phases: pretreatment, last week of HCTZ, week KMgCit group took KMgCit three tablets with breakfast 1, week 2, and week 3 of supplement with HCTZ) was and three tablets with dinner, delivering 42 mEq K, 21 used to assess differences in response between the two mEq Mg, and 63 mEq citrate per day for three weeks. study groups. A significant interaction between treat- Those in the potassium chloride group received three ment and phase (visit) indicates that the responses to the tablets of potassium chloride with breakfast and three different treatments are not the same. Within a treatment tablets with dinner, providing 42 mEq of potassium and group, multiple comparisons were made by using paired chloride each day for three weeks. t-tests to compare the last week of HCTZ phase with Each tablet of KMgCit contained 7 mEq K, 3.5 mEq each week of supplement phase (HCTZ plus KMgCit Mg, and 10.5 mEq citrate; a tablet of potassium chloride or potassium chloride) and with the pretreatment phase. contained 7 mEq each of potassium and chloride. Identi- For interpreting these multiple comparisons, a signifi- Wuermser et al: KMgCit versus potassium chloride in hypokalemia 609

Table 1. Baseline presentations of 60 subjects Serum chemistries Potassium On HCTZ alone, 44 of 60 subjects (23 in KMgCit and KMgCit chloride 21 in potassium chloride) developed hypokalemia. The No. subjects 30 30 mean serum potassium concentration significantly de- No. female/no. male 22/8 23/7 Age years 36Ϯ13 35Ϯ10 creased by 0.72 mEq/L in the KMgCit group and by 0.67 Weight kg 77Ϯ13 82Ϯ20 mEq/L in the potassium chloride group (Fig. 1A). During Height cm 171Ϯ101 167Ϯ12 the supplement phase, the serum potassium concentra- Serum Potassium mEq/L 4.2Ϯ0.4 4.1Ϯ0.5 tion increased significantly by 0.34 to 0.43 mEq/L in the Magnesium mg/dL 2.0Ϯ0.2 2.0Ϯ0.2 KMgCit group and by 0.35 to 0.44 mEq/L in the potas- Urinary sium chloride group. The serum potassium concentration Potassium mEq/day 52Ϯ22 44Ϯ14 Magnesium mg/day 92Ϯ51 91Ϯ34 was maintained within normal limits or was normalized pH 6.05Ϯ0.47 6.09Ϯ0.38 (Ͼ3.5 mEq/L) in 76 and 71% of determinations in the Citrate mg/day 640Ϯ299 587Ϯ238 KMgCit and potassium chloride groups, respectively. No Endogenous Cr 119Ϯ33 121Ϯ34 Clearance mL/min significant difference was disclosed between the two Abbreviation is: Cr, creatinine. To convert urinary magnesium to mEq/day, groups. divide value in mg/day by 12.16. To convert citrate to mEq/day, divide value in During treatment with HCTZ alone, the mean serum mg/day by 63. Hypokalemia ϭ serum potassium Յ3.5 mEq/L; hyperkalemia ϭ serum potassium Ͼ5.5 mEq/L; hypomagnesemia ϭ serum magnesium Յ1.5 mEq/L chloride concentration decreased significantly in both or 1.8 mg/dL. groups (Fig. 1B). When KMgCit was added, a significant increase in serum chloride concentration was disclosed at three weeks but not during the first two weeks. The serum chloride concentration increased significantly to- cance level of 0.01 was used to adjust for multiplicity of ward the prethiazide range during all three weeks of testing. potassium chloride supplementation from HCTZ alone. For side effect frequency and severity scores, the Wil- With both supplementations, the serum chloride concen- coxon signed-rank test was performed for the compari- son of HCTZ alone within each group, and the Wilcoxon tration remained below the prethiazide values. Differ- Rank Sum statistic was employed for comparing KMgCit ences between the two groups were significant during with potassium chloride. The 0.05 level of significance the supplement phase (analysis of variance, P Ͻ 0.01). was used for these comparisons to avoid a type II error. Treatment with HCTZ alone significantly increased Results are presented as mean Ϯ sd. Analyses were serum bicarbonate concentration in both groups (Fig. performed by using SAS version 6.12 (SAS Institute, 1C). During KMgCit supplementation, the serum bicar- Cary, NC, USA). bonate concentration significantly decreased at three weeks from HCTZ alone but not during the first two weeks. In contrast, potassium chloride supplementation RESULTS significantly decreased serum bicarbonate concentration Demography and baseline presentation during all three weeks. The change in serum bicarbonate Sixty-five subjects were enrolled in the trial, allowing concentration was significantly different between the two for an anticipated withdrawal of five subjects. A decision groups (ANOVA, P ϭ 0.01). was made to close the trial in mid-December 1998 when The mean serum magnesium concentration did not 60 subjects completed all three weeks of the supplement decrease significantly during HCTZ alone in either group phase. During the first week of HCTZ alone, two subjects (Fig. 1D). During supplement phase, the addition of withdrew because of side effects of thiazide, and one KMgCit to the ongoing HCTZ treatment produced a subject withdrew because of an unwillingness to follow small but significant increase in serum magnesium con- the diet. The fourth subject withdrew before starting centration of 0.11 to 0.12 mEq/L. In contrast, serum HCTZ from an exacerbation of pre-existing spastic coli- magnesium concentration did not change significantly or tis. The fifth subject had successfully finished three weeks decreased marginally during potassium chloride supple- of HCTZ phase in mid-December 1998. We decided to mentation (P ϭ 0.07 at 2 weeks). During the supplement withdraw her from the trial, anticipating difficulty in phase, the serum magnesium concentration was signifi- adherence to the diet during the holiday season. cantly different between the two groups (ANOVA, P ϭ Demographic and baseline data are presented for 60 0.0002). subjects who completed the trial in Table 1. There were 30 subjects in each group (KMgCit or potassium chlo- Urinary chemistries ride). The two groups did not differ with respect to gen- The mean urinary pH did not change significantly on der ratio, age, weight, and height. Serum and urinary HCTZ alone (Table 2). During the supplement phase, chemistries did not differ between the two groups. it increased significantly when KMgCit was added to the 610 Wuermser et al: KMgCit versus potassium chloride in hypokalemia

Fig. 1. (A) Effect of potassium-magnesium citrate (KmgCit; ᭹) and potassium chloride (᭺) on serum potassium concentration. After hypokalemia developed from treatment with hydrochlorothiazide (HCTZ) alone, supplementation with either KMgCit or potassium chloride was provided for three weeks while HCTZ was continued. Within each group, the significance of difference from HCTZ alone was determined. †P Ͻ 0.001 from HCTZ alone within the same groups. (B) Effect of KMgCit or potassium chloride on serum chloride concentration. *P Ͻ 0.05 from HCTZ alone within the same group. (C) Effect of KMgCit or potassium chloride on serum bicarbonate concentration. **P Ͻ 0.01 from HCTZ alone within the same group. (D) Effect of KMgCit or potassium chloride on the serum magnesium concentration.

ongoing HCTZ treatment by about 0.6. In contrast, no Safety and other results significant change in urinary pH developed during potas- Individual gastrointestinal scores were one (lowest sium chloride supplementation. Differences between the value) or close to one throughout the study (prethiazide, two groups were significant (ANOVA, P Ͻ 0.0001). HCTZ alone, and supplement phase) in both KMgCit The mean urinary citrate decreased significantly in and potassium chloride groups. There was a small but sig- both groups during HCTZ alone (Table 2). It increased nificant increase in scores for nausea, anorexia, and con- significantly during supplementation with KMgCit (by stipation from prethiazide to HCTZ alone by about 0.2 about 260 mg/day), but not with potassium chloride. Be- unit (P Ͻ 0.05). No significant difference in frequency and tween-group differences during supplementation were significant (ANOVA, P ϭ 0.0004). severity scores for any side effect was disclosed between Urinary magnesium increased significantly by about HCTZ alone and supplement phase in either group. 25 mg (2.1 mEq)/day following KMgCit supplementation On HCTZ alone, individual scores for muscle weak- (P Ͻ 0.01), but did not change significantly after potas- ness, muscle cramping, and dizziness increased signifi- sium chloride supplementation (Table 2). Differences cantly by 0.2 to 0.5 unit in both groups (P ϭ 0.05 to between the two groups were significant (ANOVA, P ϭ 0.001). Scores for muscle weakness and cramping de- 0.0007). Urinary potassium increased significantly fol- creased significantly during supplementation with KMgCit lowing supplementation with KMgCit supplementation from HCTZ alone (P ϭ 0.05 to 0.01). The scores for (P Ͻ 0.001) and potassium chloride (P Ͻ 0.05). muscle weakness and dizziness declined significantly fol- Wuermser et al: KMgCit versus potassium chloride in hypokalemia 611

Table 2. Urinary response found to be equally effective as potassium chloride in Potassium correcting or ameliorating hypokalemia. However, un- KMgCit chloride like potassium chloride, KMgCit produced a small but N Mean SD N Mean SD significant increase in serum magnesium concentration Urinary pHd by providing bioavailable magnesium and exerted alka- Pretreatment 29 6.05Ϯ0.47 30 6.09Ϯ0.38 linizing and citraturic actions. Both KMgCit and potas- Last week of HCTZ alone 30 5.96Ϯ0.34 30 5.96Ϯ0.43 sium chloride were well tolerated, with both supplements Week 1 of supplement 29 6.50Ϯ0.39c 30 5.96Ϯ0.42 Week 2 of supplement 29 6.55Ϯ0.43c 30 5.97Ϯ0.45 ameliorating adverse symptoms of thiazide treatment. Week 3 of supplement 30 6.56Ϯ0.43c 30 5.96Ϯ0.48 The equal efficacy of KMgCit and potassium chloride d Urinary citrate mg/day in correcting thiazide-induced hypokalemia allays con- Pretreatment 29 640Ϯ299a 30 587Ϯ238b Last week of HCTZ alone 30 502Ϯ245 30 462Ϯ192 cern that the provision of chloride anion with potassium Week 1 of supplement 28 718Ϯ349c 30 511Ϯ208 supplementation is critical for the restoration of normal c Week 2 of supplement 29 768Ϯ338 30 537Ϯ231 serum potassium concentration. When a citrate anion is Week 3 of supplement 30 764Ϯ314c 30 523Ϯ199 Urinary Mgd mg/day provided as with KMgCit, an earlier study [14] suggested Pretreatment 29 92Ϯ51 30 91Ϯ34 that a relatively poor renal tubular reabsorption of ci- Last week of HCTZ alone 30 88Ϯ37 30 89Ϯ40 trate would cause an enhanced renal tubular secretion Week 1 of supplement 29 110Ϯ62b 30 82Ϯ27 Week 2 of supplement 29 117Ϯ52c 30 88Ϯ37 of potassium, impairing the correction of hypokalemia. Week 3 of supplement 30 115Ϯ54b 30 90Ϯ37 However, a more recent study has disclosed that renal Urinary K mEq/day potassium leak occurs only in the setting of severe chlo- Pretreatment 29 52Ϯ22 30 44Ϯ14 Last week of HCTZ alone 30 48Ϯ22 30 48Ϯ24 ride depletion with urinary chloride concentration of less Week 1 of supplement 29 67Ϯ31c 30 62Ϯ26a than 15 mEq/L [15]. Such severe chloride depletion is c a Week 2 of supplement 29 71Ϯ30 30 62Ϯ29 rare, except in intractable diarrhea or vomiting or follow- Week 3 of supplement 30 75Ϯ31c 30 55Ϯ24 Urinary Na mEq/day ing protracted nasogastric suction. A significant chloride Pretreatment 29 146Ϯ61a 30 157Ϯ83 depletion did not develop in our study, as urinary chlo- Last week of HCTZ alone 30 175Ϯ52 30 151Ϯ75 ride exceeded 50 mEq/day in a vast majority of our Week 1 of supplement 29 167Ϯ63 30 181Ϯ102 Week 2 of supplement 29 186Ϯ87 30 190Ϯ84a subjects (unpublished observation). This finding could Week 3 of supplement 30 199Ϯ108 30 194Ϯ107a explain the similar efficacy of KMgCit and potassium Urinary Cl mmol/day chloride in correcting hypokalemia. Pretreatment 29 138Ϯ60a 30 152Ϯ89 Last week of HCTZ alone 30 167Ϯ46 30 155Ϯ72 Both KMgCit and potassium chloride displayed a pic- Week 1 of supplement 29 157Ϯ55 30 209Ϯ138a ture of mild metabolic alkalosis, with an incomplete re- b Week 2 of supplement 29 172Ϯ79 30 210Ϯ87 turn of serum concentrations of bicarbonate and chloride Week 3 of supplement 30 187Ϯ100 30 203Ϯ107a to the prethiazide values. The persistence of hypoka- During 3 weeks of supplement phase, KMgCit or potassium chloride was given with HCTZ. lemia in some patients and probable prevailing volume Significant difference from HCTZ alone is shown by a for P Ͻ 0.05, b for P Ͻ depletion during a short-term thiazide therapy of four 0.01 and c for P Ͻ 0.001 d KMgCit versus potassium chloride (ANOVA), P Ͻ 0.001; urinary K, P ϭ to six weeks could partly account for mild metabolic 0.07; Na & Cl, P Ͼ 0.10 alkalosis in both groups. The more prolonged delay in the correction of hyperbicarbonatemia and hypochloridemia by KMgCit, compared with potassium chloride, could lowing potassium chloride supplementation (P ϭ 0.05 to be explained by the provision of citrate anion rather 0.01). than chloride anion, and delivery of an alkali load [8]. By pill count, compliance averaged 100% for HCTZ, The presence of mild metabolic alkalosis during 96% for KMgCit, and 98% for potassium chloride. One KMgCit supplementation should not pose a deleterious subject from the potassium chloride group had a positive clinical problem. Serum concentrations of bicarbonate test for occult blood in feces during the supplement and chloride were within normal limits during KMgCit phase, without anemia or symptoms of blood loss. Re- supplementation. Small changes in serum bicarbonate peat testing was negative. No other subject had a positive and chloride shown with KMgCit in this trial have been test for occult blood in feces. Electrocardiograms, ob- encountered during potassium citrate or potassium bi- tained when serum potassium was less than 3 mEq/L, carbonate therapy of patients with urolithiasis [16], hy- did not show abnormal changes. pertension [17], or of postmenopausal women (for pre- vention of bone loss) [17], without known side effects. The alkalinizing and citraturic effects displayed by DISCUSSION KMgCit, but not by potassium chloride, justify the use This trial was undertaken in order to compare the of potassium alkali over potassium chloride in patients value of KMgCit with potassium chloride in the manage- with hypercalciuric nephrolithiasis treated with thiazide. ment of thiazide-induced hypokalemia. KMgCit was KMgCit not only prevents hypokalemia but increases 612 Wuermser et al: KMgCit versus potassium chloride in hypokalemia urinary citrate, an important inhibitor of the crystalliza- Reprint requests to Lisa-Ann Wuermser, M.D., Center for Mineral Metabolism and Clinical Research, University of Texas, Southwestern tion of stone-forming calcium salts. Moreover, KMgCit Medical Center; 5323 Harry Hines Boulevard, Dallas, Texas 75390- should be more useful than potassium citrate. Unlike 8885, USA. potassium citrate, KMgCit increases urinary magnesium E-mail: [email protected] [9], thereby lowering urinary saturation of calcium oxa- late from magnesium-oxalate complexation. KMgCit REFERENCES should also inhibit bone loss in postmenopausal women 1. Yendt ER, Guay GF, Garcia DA: Use of thiazide in the preven- by delivering an alkali load, as has been shown for potas- tion of renal calculi. Can Med Assoc J 102:614–620, 1970 2. Morgan DB, Davidson C: Hypokalemia and diuretics: An analysis sium bicarbonate [17]. of publications. Br Med J 280:905–908, 1980 A potential advantage of KMgCit over potassium 3. Dycker T, Wester PO: Intracellular magnesium loss after diuretic administration. Drugs 28:161–166, 1984 chloride is its capability for preventing thiazide-induced 4. Nicar MJ, Peterson R, Pak CYC: Use of potassium citrate as magnesium depletion. Unfortunately, no one developed potassium supplement during thiazide therapy of calcium nephroli- hypomagnesemia during the short duration of HCTZ thiasis. J Urol 131:430–433, 1984 5. Iseri LT: Role of magnesium in cardiac tachyarrhythmia. Am J treatment of four to six weeks. However, a small but Cardiol 65:45K–50K, 1990 significant increase in serum magnesium concentration 6. Whang R, Flink EB, Dycker T, Wester PO, Aikawa JK, Ryan occurred during KMgCit supplementation, despite con- MP: Magnesium depletion as a cause of refractory potassium deple- tion. Arch Intern Med 145:1686–1689, 1985 tinuing HCTZ therapy, whereas serum magnesium con- 7. Pak CYC, Peterson R, Sakhaee K, Fuller C, Preminger G, centration showed a marginal decline with potassium Reisch J: Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in chloride. Moreover, urinary magnesium significantly in- thiazide-unresponsive hypercalciuric nephrolithiasis. Am J Med creased in the setting of a small rise in serum magnesium, 79:284–288, 1985 indicating that KMgCit delivered bioavailable magne- 8. Sakhaee K, Alpern R, Jacobson HR, Pak CYC: Contrasting effects of various potassium salts on renal citrate excretion. J Clin sium. Although the findings from this trial suggests that Endocrinol Metab 72:396–400, 1991 prevention of magnesium depletion by KMgCit is likely, 9. Pak CYC, Koenig K, Khan R, Haynes S, Padalino P: Physico- a full confirmation would require a long-term trial with chemical action of potassium-magnesium citrate in nephrolithiasis. J Bone Miner Res 7:283–287, 1992 HCTZ treatment of sufficient duration to allow the de- 10. Ettinger B, Pak CYC, Citron JT, Vangessel A: Potassium mag- velopment of hypomagnesemia or magnesium depletion. nesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol 158:2069–2073, 1997 In this trial, neither KMgCit nor potassium chloride 11. Ruml LA, Wuermser LA, Poindexter J, Pak CYC: The effect of completely corrected thiazide-induced hypokalemia. This varying molar ratios of potassium-magnesium citrate on thiazide- finding is probably due to the relatively high dose of induced hypokalemia and magnesium loss. J Clin Pharmacol 38:1035–1041, 1998 HCTZ used and the measurement of serum potassium 12. Ruml LA, Gonzalez G, Taylor RN, Wuermser LA, Pak CYC: 4.5 hours after the last dose of HCTZ when its action is Effect of varying doses of potassium-magnesium citrate on thia- expected to be maximal. Moreover, this trial did not zide-induced hypokalemia and magnesium loss. Am J Ther 6:45–50, 1999 include a placebo group. However, the denial of potas- 13. Ruml LA, Pak CYC: The effect of potassium-magnesium citrate sium supplement to normal subjects on HCTZ was con- on thiazide-induced hypokalemia and magnesium loss: Compari- son with potassium citrate and magnesium citrate. Am J Kidney sidered to be ethically unacceptable. Past studies indi- Dis 34:107–113, 1999 cated that hypokalemia persists after it develops during 14. Kassirer JP, Berkman PM, Lawrenz DR, Schwartz WB: The chronic thiazide therapy if potassium supplementation critical role of chloride in the correction of hypokalemic alkalosis in man. Am J Med 38:172–189, 1965 is not provided [2]. 15. Carlisle EJF, Donnelly SM, Ethier JH, Quaggin SE, Kaiser In summary, the effects of KMgCit could be clearly UB, Vasuvattakul S, Kamel KS, Halperin ML: Modulation of the secretion of potassium by accompanying anions in humans. distinguished from potassium chloride. KMgCit should Kidney Int 39:1206–1212, 1991 therefore be advantageous over potassium chloride as 16. Pak CYC, Fuller C, Sakhaee K, Preminger GM, Britton F: an adjunctive agent in patients treated with thiazide. Long-term treatment of calcium nephrolithiasis with potassium citrate. J Urol 134:11–19, 1985 17. Sebastian A, Harris ST, Ottaway JH, Todd KM, Morris RC: ACKNOWLEDGMENTS Effect of potassium bicarbonate on mineral balance and skeletal metabolism in postmenopausal women. N Engl J Med 330:1776– This work was supported by National Institutes of Health grants 1781, 1994 P01-DK20543, M01-RR00633, and K30-HL04091 and by a grant from 18. Morris RC Jr, Schmidlin O, Tanaka M, Forman AH, Frassetto the Mission Pharmacal Company. The authors would like to thank L, Sebastian A: Differing effects of supplemental KCl and KHCO3: Beverley Adams-Huet, M.S., for biostatistical support, and RueNell Pathophysiological and clinical implications. Semin Nephrol 5:487– Taylor, R.N., for nursing support. 493, 1999