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If you had unlimited resources, what nephrology clinical trial would you conduct? That's the big idea behind DreamRCT, a project of UKidney created by Joel Topf, MD, and Jordan Weinstein, MD, in partnership with 番茄社区. Vote for your favorite trial at

Introduction

Calcium phosphate stones are common, making up about of all calcium stones. The definition of such stones is usually a stone with at least 50% calcium phosphate or more.

Most often, calcium phosphate appears in the form of hydroxyapatite, the crystal found in bone. Other calcium phosphate crystals include brushite and carbonate apatite. The latter sometimes implies the presence of urinary tract infection, which should be sought and ruled out.

The cause of calcium phosphate stones is often obscure, but is most often related to an unexplained high urine pH level. While this high urine pH, in association with calcium stones, may be related to , that diagnosis is not often made as it requires ammonium chloride loading, a test that is not often performed in the U.S.

Such patients would often have hypocitraturia. At present, the difference between calcium oxalate and calcium phosphate stone formers appears to simply be the difference in urine pH, without convincing evidence that the difference is dietary or genetic.

In , calcium phosphate stones were seen in young women in particular. Predominant calcium phosphate stones should also lead to consideration of primary hyperparathyroidism, though calcium oxalate stones are actually more common in that disorder. Carbonic anhydrase inhibitors, such as acetazolamide and topiramate (Topamax), are also due to the ensuing bicarbonaturia.

Treatment of calcium phosphate stones is controversial because the use of citrate is not backed by any trials. Of course, nonspecific stone prevention regimens must be prescribed before considering the appropriateness of citrate supplementation. Increased fluid intake to 96 oz (about 3 L) is always appropriate. Dietary sodium restriction to 100 mEq (about 2.5 g) may help reduce urine calcium excretion.

When I give a talk on kidney stones, the question most often asked is whether citrate administration is associated with calcium phosphate stones and how calcium phosphate stones should be treated. This controversy about the use of alkali is long-standing.

Citrate binds calcium, forming a soluble complex, and prevents oxalate and phosphate from binding to calcium. One can think of citrate as a competitive antagonist of calcium stone formation. Citrate also prevents aggregation and agglomeration of crystals. These effects are not reflected by an effect of citrate on the urinary supersaturation of calcium salts. In addition, alkali often reduces urinary calcium excretion, an effect which is attributed to reduction of bone turnover and to stimulation of calcium absorption in the distal tubule.

However, citrate is metabolized by the liver and kidney via a process which consumes a proton, the equivalent of generating bicarbonate. The result is an increase in urine pH. As urine pH increases, monobasic phosphate (with one negative charge) in the urine has a proton titrated off, forming the dibasic phosphate with two negative charges. The two negative charges make the molecule very favorable for pairing with the divalent cation, calcium. This increase leads to an increase in the supersaturation of calcium phosphate.

In other words, while citrate in the urine may antagonize calcium stone formation, whether oxalate or phosphate, it also will lead to an increase in urine pH which might instead increase forces favoring calcium phosphate stone formation.

Background

The clinical evidence is slight. Some anecdotal studies demonstrate that renal tubular acidosis is effectively treated with alkali. In a series of patients treated for renal tubular acidosis (RTA), "it has long been recognized that alkali is beneficial for patients with Type I RTA." He also stated that "reluctance to use alkali therapy for renal stones was probably due to concerns over the effect of increased urine pH to increase the relative saturation ratio of brushite."

Affected patients may benefit particularly because they have a low serum bicarbonate and hypocitraturia, but the urine pH is certainly elevated to begin with. In another of citrate for RTA-associated stones, the favorable effect was a 91.2% reduction in new stones from before to after treatment for 34 months (13.1 per year to 1.2 per year). Urine pH rose from 6.5 to 7.0, urine citrate from 292 to 494 mg/day, and the relative saturation of brushite did not change.

In addition, of citrate administration to calcium stone formers separated patients into those whose urine pH went up to greater than 6.5 with citrate administration and those whose urine was lower than 6.5. There was no difference in the effectiveness of citrate for stone prevention in these two groups, regardless of whether urine pH went up or not. Of course these were not exclusively calcium phosphate stone formers so the result might not apply as nicely if that was the included population. However, some proportion of the study group is likely to have had calcium phosphate stones, and certainly the formation of calcium phosphate stones might have negated the effect of the citrate.

One safe way to administer potassium citrate to calcium stone formers might be to also prescribe thiazides to reduce urine calcium excretion. This regimen might allow the practitioner to feel safer about the prescription of the citrate and the concomitant increase in urine pH, as the fall in urine calcium would help reduce the increase in supersaturation resulting from the increase in urine pH.

The Trial

My dream RCT is not difficult then to imagine. Patients with recurrent calcium phosphate stones would be included. A history of at least two stones would be preferred. Patients with low serum bicarbonate at baseline would be excluded, as would patients with estimated glomerular filtration rates below 60 ml/min/1.73m².

Baseline noncontrast, low-dose CT scans would be performed in all participants. Twenty-four hour urine collections on the patients' self-selected diets would be performed.

The participants would then be randomly assigned to one of two regimens:

• Counseling regarding sodium restriction and fluid intake plus two placebo tablets twice a day (control group)
• 20 mEq of potassium citrate twice a day plus counseling regarding sodium restriction and fluid intake (active intervention group)

Twenty-four hour urine collections would be performed yearly as would repeat CT scanning. All stone episodes, including emergency room visits, urological interventions, and spontaneous stone passage would be recorded. The patients would do a yearly stone episode questionnaire.

At the end of 3 years, the primary outcome -- the recurrence of new stones -- would be assessed, summing the results of monitoring for both asymptomatic and symptomatic stones.

, () is professor of medicine & physiology and clinical chief of nephrology at New York University Langone Medical Center in New York City. He has had three CaOx monohydrate stones.