HIGHER URINARY POTASSIUM IS ASSOCIATED WITH DECREASED STONE GROWTH AFTER SHOCK WAVE LITHOTRIPSY

0022-5347/00/1645-1486/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 164, 1486 –1489, November 2000 Printed in U.S.A.

HIGHER URINARY POTASSIUM IS ASSOCIATED WITH DECREASED STONE GROWTH AFTER SHOCK WAVE LITHOTRIPSY ANDREAS PIERRATOS, NAFISA DHARAMSI, LESLEY K. CARR, DOMINIQUE IBANEZ, MICHAEL A. S. JEWETT AND R. JOHN D’A. HONEY* From the Department of Medicine, Humber River Regional Hospital, Division of Urology, St. Michael’s Hospital, Division of Urology, Sunnybrook and Women’s Health Sciences Centre, Division of Urology, Toronto Hospital and University of Toronto, Toronto, Ontario, Canada

ABSTRACT

Purpose: We correlated serum and urinary biochemical parameters with radiological evidence of stone growth after shock wave lithotripsy. Materials and Methods: Biochemical parameters in serum and 24-hour urine collections of 359 patients were correlated with stone growth for 2 years after shock wave lithotripsy. Each patient underwent a minimum of 2 radiological studies at 3 and 12 months and plain abdominal x-ray at 24 months. The presence and size of stones were documented by a radiologist in blinded fashion. Stone growth was defined as measurable growth of a preexisting stone or new stone formation. Results: A total of 209 patients remained stone-free or had no existing stone growth, while stone size decreased in 30. Of the remaining 120 patients with stone growth 72 had new growth and 48 had growth of preexisting stones. Urinary excretion of potassium was significantly higher in those without than with stone growth (mean 24-hour urine collection plus or minus standard deviation 62 ⫾ 27 versus 54 ⫾ 23 mmol., p ⫽ 0.009). The only parameter significantly associated with stone growth was urinary potassium. Linear regression revealed that for each 10 unit increase in urinary potassium there was a corresponding 2 mm. decrease in stone growth (p ⫽ 0.013). Conclusions: Our results indicate that increased urinary potassium excretion correlates with a decreased risk of stone growth up to 2 years after shock wave lithotripsy, implying that a high potassium diet may be beneficial for preventing stone growth. The effect of potassium supplementation on stone formation and growth must be investigated further. KEY WORDS: kidney, lithotripsy, kidney calculi, urinary calculi

The introduction of shock wave lithotripsy revolutionized the management of renal stones. The value of shock wave lithotripsy is due to its relatively high efficacy and low morbidity but concern remains regarding the possible increase in new stone formation after treatment. Such increases have been compared to those of nonfragmentation modalities of stone removal1 and recurrence has been reported as high as 50% within 1 year after shock wave lithotripsy.2 To minimize new stone formation after therapy an understanding of serum and urine parameters may enable biochemical manipulation to change the natural history of stone disease. Others have correlated various serum parameters with calculi formation, including calcium,3 phosphate3 and potassium.4, 5 Similarly studies have also shown significant differences in urinary parameters in patients with renal calculi when focusing on urinary calcium,6 –12 citrate,5, 6, 11, 13 potassium,8 copper,14 phosphorus,14 uric acid,15, 16 magnesium17 and oxalate excretion.11, 18 We assessed independent biochemical variables in serum and 24-hour urine collections in a large prospective study, and correlated them with radiological evidence of stone growth after shock wave lithotripsy. MATERIALS AND METHODS

Prospective data were collected from the initial 1,000 patients consecutively treated for renal and ureteral stones with a Siemens Lithostar† at our institution. Of the initial

1,000 patients treated with lithotripsy by Psihramis et al 217 men and 142 women with an average age of 51.5 ⫾ 14 years underwent complete serum and urine metabolic evaluation for radiography correlation with stone growth.19 We obtained 24-hour urine collections and determined serum parameters on the day before shock wave lithotripsy and on the treatment day. Specifically we measured the serum concentration of sodium, potassium, chloride, carbon dioxide, total and ionized calcium, phosphate, magnesium, uric acid, urea, creatinine and creatinine clearance. Parathyroid hormone was determined only when ionized calcium was greater than 1.27 mmol./l. (normal 1.15 to 1.30). Also required was 24-hour urine collection for documenting sodium, potassium, chloride, citrate, oxalate, total calcium, phosphate, magnesium, uric acid, creatinine, creatinine clearance, pH and urine volume. Urine collection bottles contained thymol crystals dissolved in isopropanol as a preservative. Serum sodium, potassium, chloride, total carbon dioxide, creatinine, urea, calcium, magnesium, inorganic phosphorus, uric acid and ionized calcium, and urinary sodium, potassium, chloride, creatinine oxalate and citrate were analyzed on commercially available analyzers. For urinary oxalate and citrate we used commercially available reagents. We calculated calcium oxalate and the brushite relative saturation rates using computer software.20 Radiological data included plain x-ray of the kidneys, ureters and bladder and tomography at 3 and 12 months, and plain x-ray of the kidneys, ureters and bladder at 24 months. All radiological studies were read by a radiologist in blinded fashion. Stone growth was defined radiologically as any increase in the size

Accepted for publication June 9, 2000. * Requests for reprints: Division of Urology, St. Michael’s Hospital, 61 Queen St. E., Suite 9103Q, Toronto, Ontario M5C 2T2, Canada. † Siemens Medical Systems, Inc., Iselin, New Jersey. 1486

HIGHER URINARY POTASSIUM AND DECREASED STONE GROWTH

of a preexisting stone in mm. or new stone formation. We also reviewed the records of 210 consecutive patients previously treated at our lithotripsy unit with thiazide, which may have affected laboratory parameters. Patients from the original group of 1,000 were excluded from study when simultaneous laboratory and radiological data were not available or they underwent fewer than 2 radiological evaluations during the study period. In addition, we excluded those with primary hyperparathyroidism and uric acid stones. Using computer software statistical analysis was completed for each variable assessed by multiple linear regression analysis and t tests. RESULTS

In this study stone status was determined up to 2 years after shock wave lithotripsy (table 1). Of the 359 study patients 280 (78%) were followed for the 24-month study duration, while 79 (22%) had only 12 months of followup. Mean followup plus or minus standard deviation of those in the no growth and growth groups was 21 ⫾ 5 and 22 ⫾ 4 months, respectively (p ⫽ 0.015). There was no significant correlation of urinary potassium output with the duration of subsequent followup (r ⫽ ⫺0.011, p ⫽ 0.80). Of the 359 patients treated with shock wave lithotripsy 120 had new stones or a stone growth of 5.08 ⫾ 4.55 mm. (range 1 to 27) in the 2-year period. Tables 2 and 3 show serum chemistry study and 24-hour urine collection results with test of significance adjusted for patient age and sex. The difference in mean urinary citrate in the groups without and with stone growth approached statistical significance (2.6 ⫾ 1.6 versus 2.3 ⫾ 1.5 mmol./24 hours, p ⫽ 0.081). Mean urinary potassium output was significantly higher in the 24-hour urine collection of patients without than with stone growth 24 months after therapy (62 ⫾ 27 versus 54 ⫾ 23 mmol./24 hours, p ⫽ 0.009). Multiple linear regression analysis demonstrated that for each 10 mmol. decrease in dietetic potassium intake there was a corresponding 0.2 mm. increase in stone growth (p ⫽ 0.013). The rest of the urine as well as the serum chemistry studies showed no significant difference in the 2 groups, and did not correlate with stone growth. The calculated calcium oxalate and brushite supersaturation values were not different in the 2 groups (table 4). Only 4 of the 210 consecutive patients (1.9%) treated in the lithotripsy unit whose charts were reviewed were taking thiazides. DISCUSSION

In our study 24-hour urine collections indicated a marginally significant increase in citrate but a highly significant increase in potassium excretion (p ⫽ 0.081 and 0.009, respectively) in patients who remained stone-free or had no growth of existing stones 24 months after shock wave lithotripsy. This finding implies that urinary potassium excretion may be an independent factor affecting stone recurrence. Followup was longer for stone formers, which is not surprising since stone formation or growth would more likely be detected by longer followup. The association of stone growth with urinary potassium was not related to longer followup of stone formers because urinary potassium did not correlate with the duration of followup. Less than 2% of the 210 consecutive patients

TABLE 1. Outcome of shock wave lithotripsy up to 24 months after treatment No. Pts. Total treated Stable with no growth or new stone formation Decreased stone size New stones Increased stone size

359 209 30 72 48

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reviewed were on thiazide diuretics and, therefore, it is unlikely that this medication had any role in our findings. Others have studied the effect of changes in serum potassium or the administration of potassium salts on urinary inhibitors and promoters of renal calculi as well as on stone formation. Early studies showed that hypokalemia decreased the urinary excretion of citrate as a result of intracellular acidosis of the renal tubular cells. Therefore, the benefit of high dietetic potassium on stone formation implied by our study may possibly be explained by increased urinary citrate. Since the correlation of urinary citrate with stone formation was only marginal, this explanation is unlikely. The value of potassium citrate therapy for preventing calculi is well recognized21 and this medication has become a valuable treatment option.22 In all relevant studies it was assumed that the citrate anion conferred a protective effect on stone formation. To our knowledge the possibility that part of the beneficial effect of potassium citrate on stone formation is related to a direct effect of the potassium ion has not been previously considered. Interestingly in our study the correlation of stone formation with urinary potassium was stronger than the correlation with urinary citrate. Sakhaee et al also reported that potassium citrate is more effective for decreasing urinary calcium excretion than an equivalent dose of sodium citrate.21 This effect was attributed to the known hypercalciuric effect of sodium rather than to any effect of potassium. Nicar et al observed that potassium bicarbonate also decreased urinary calcium excretion and was more effective than sodium bicarbonate.23 This hypocalciuric effect of potassium bicarbonate was likely due to its alkalizing effect and the resulting decrease in unfilterable serum ionized calcium. When sodium bicarbonate was given, the hypocalciuric effect was blunted by the hypercalciuric effect of sodium. A direct hypocalciuric effect of the potassium ion was not implied in these studies. Notably in our series urinary calcium did not correlate with stone formation. Tungsanga et al noted a high prevalence of hypokalemia, hypokaliuria and hypocitruria in stone formers, and raised the possibility that potassium depletion was a contributing factor.5 Although the results of their study were consistent with our observation that urinary potassium is important for stone formation, they included patients in whom significant potassium depletion affected urinary citrate. Our series demonstrated that dietary potassium may be important in patients without laboratory evidence of potassium depletion and, therefore, our results may be more generalized. Lemann et al reported a positive correlation of an elevated urinary sodium-to-potassium ratio with subsequent stone formation, which was associated with elevated urinary saturation of calcium phosphate and monosodium urate as well as decreased urinary citrate.24 The importance of the sodiumto-potassium ratio is consistent with our findings, although we did not observe a correlation of urinary sodium with stone recurrence. Curhan et al described the effect of dietary potassium on stone formation in a large prospective study of nonstone formers.8, 9 They reported that high dietary calcium intake decreased the risk of initial kidney stone formation by 34%, while a high potassium intake was associated with an even more dramatic 51% decrease in the risk of stone formation. High protein intake was associated with an increased risk of stone formation. Interestingly although potassium had the strongest effect, it received little subsequent attention from the scientific and lay press. The study of Curhan et al was based on dietetic records. Our series demonstrated the strong association of dietetic potassium with stone formation more directly by the measurement of urinary potassium. Furthermore, we confirmed the importance of this association in a group of recurrent stone formers, for whom this information is even more important than in the nonstone forming population evaluated by Curhan et al.

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HIGHER URINARY POTASSIUM AND DECREASED STONE GROWTH TABLE 2. Serum parameters determined on the day of shock wave lithotripsy

Carbon dioxide (mmol./l.) Total calcium (mmol./l.) Ionized calcium (mmol./l.) Potassium (mmol./l.) Magnesium (mmol./l.) Phosphate (mmol./l.) Urea (mmol./l.) Creatinine (mmol./l.) Creatinine clearance (ml./min./1.73 m.2)

Mean Stone Growth ⫾ SD

No. Pts.

Mean No Stone Growth ⫾ SD

No. Pts.

p Value (test of significance adjusted for age and sex)

26 ⫾ 2 2.33 ⫾ 0.13 1.25 ⫾ 0.06 4.3 ⫾ 0.5 0.83 ⫾ 0.07 1.05 ⫾ 0.16 5.2 ⫾ 1.6 91 ⫾ 43 1.76 ⫾ 0.64

209 209 202 209 209 209 209 209 219

26 ⫾ 2 2.31 ⫾ 0.11 1.26 ⫾ 0.04 4.3 ⫾ 0.5 0.83 ⫾ 0.08 1.05 ⫾ 0.16 5.3 ⫾ 1.8 88 ⫾ 22 1.67 ⫾ 0.60

94 94 91 93 94 94 94 94 106

0.854 0.265 0.607 0.521 0.752 0.622 0.781 0.494 0.762

TABLE 3. Urine biochemical study results of 24-hour urine collection 1 day before shock wave lithotripsy

pH Urine vol. (ml./24 hrs.) Creatinine (mmol./24 hrs.) Citrate (mmol./24 hrs.) Potassium (mmol./24 hrs.) Magnesium (mmol./24 hrs.) Sodium (mmol./24 hrs.) Total calcium (mmol./24 hrs.) Phosphate (mmol./24 hrs.) Oxalate (␮mol./24 hrs.) Uric acid (mmol./24 hrs.)

Mean Stone Growth ⫾ SD

No. Pts.

Mean No Stone Growth ⫾ SD

No. Pts.

p Value (test of significance adjusted for age and sex)

5.95 ⫾ 0.82 1,614 ⫾ 831 13 ⫾ 5 2.6 ⫾ 1.6 62 ⫾ 27 4.1 ⫾ 1.8 152 ⫾ 74 5.5 ⫾ 3.1 28 ⫾ 11 347 ⫾ 138 3.3 ⫾ 1.6

236 239 239 238 239 238 239 238 239 238 231

5.99 ⫾ 0.80 1,615 ⫾ 689 12 ⫾ 4 2.3 ⫾ 1.5 54 ⫾ 23 4.0 ⫾ 1.8 151 ⫾ 69 5.6 ⫾ 3.1 27 ⫾ 12 349 ⫾ 127 3.2 ⫾ 1.5

118 120 120 120 120 120 120 120 119 120 120

0.459 0.896 0.994 0.081 0.009 0.772 0.588 0.278 0.819 0.681 0.613

TABLE 4. Saturation rate of urinary calcium oxalate and brushite determined using the EQUIL computer program20 Mean Stone Growth ⫾ SD

No. Pts.

Mean No Growth ⫾ SD

No. Pts.

p Value

8.10 ⫾ 3.8 1.48 ⫾ 1.6

234 235

8.24 ⫾ 3.5 1.40 ⫾ 1.2

118 117

0.382 0.763

Calcium oxalate Calcium phosphate (brushite)

The exact mechanism by which increased dietary potassium is associated with decreased stone growth is difficult to elucidate since our results did not indicate a highly significant association with stone growth and any other parameter investigated. High potassium intake may be a surrogate for high vegetable or low protein intake. Higher vegetable intake may be protective though an unrelated mechanism, while the protective effect of lower protein intake is well established.8 If protein intake were relevant in our study, one would expect a stronger correlation of stone formation with urine uric acid, or possibly urinary calcium and urinary pH, which are known to be affected by high protein intake. However, these correlations were not noted. In addition, it is conceivable that stones continued to form in patients with higher potassium intake but passed easily at a smaller size, and so they were not detected on followup x-rays done in the 2 years after shock wave lithotripsy. This scenario would imply an association of high urinary potassium with stone clearance. Such a beneficial effect of a higher potassium diet would be desirable and consistent with the findings of Cicerello et al.13 They reported that administering sodium potassium citrate after shock wave lithotripsy increased stone fragment clearance. Although success was attributed to citrate, it is conceivable that part of this beneficial effect was due to potassium rather than to the citrate ion. CONCLUSIONS

Our results imply that high urinary potassium excretion is associated with a decreased risk of new stone formation and stone growth after shock wave lithotripsy. This finding implies a protective value of a high potassium diet at and after shock wave lithotripsy. An attempt to increase urinary potassium by potassium supplementation in stone formers may have value and must be investigated further.

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