The Conundrum of Alkali Therapy in Calcium Phosphate Stone Formers

Introduction

The role of alkali therapy in calcium phosphate stones is hotly contested, but the literature surrounding this notion is nuanced and unclear. Calcium based stones account for a large percentage of stones, the majority being calcium oxalate with the remainder as calcium phosphate stones. Calcium phosphate stones are more common in women than in men.^1,2 We will attempt to discuss the role of alkali therapy in calcium phosphate stone formers by framing our discussion around a clinical case.

Case Presentation

A 52-year-old man with no significant past medical history. His first stone was a year ago that passed spontaneously with 100% calcium phosphate (apatite) composition. Six months ago, he underwent a left ureteroscopy with a stone composition of 80% calcium phosphate (apatite) and 20% calcium oxalate. After initial metabolic work up (Table 1, Time 0), he was started on potassium citrate 10 mEq twice a day. Two months later, a repeat computed tomography showed worsening renal calcifications, and a repeat 24-hour urine was collected (T+ 2 months). Shortly thereafter, he developed acute kidney injury due to stone obstruction requiring bilateral percutaneous nephrolithotomy and ureteroscopy with stent placement. Stone analysis was consistent with 90% calcium phosphate (brushite) and 10% calcium phosphate (apatite). Because of repeated stone episodes, he was subsequently referred to nephrology. He carries a diagnosis of peptic ulcer disease and struggles with postprandial pain, making it hard to tolerate potassium citrate. He also admits to frequent diarrheal episodes related to his peptic ulcer disease. Serum chemistry shows a potassium of 4.2 mEq/l, bicarbonate of 18 mEq/l, and a creatinine of 1.4 mg/dl.

Table 1.

Urinary metabolic work up

Time	Urine Volume (L)	Urine Creatinine (mg)	SS CaOx	Urine Ca (mg)	Urine Ox (mg)	Urine Citrate (mg)	SS CaP	Urine pH
Time 0	0.99	1317	6.78	116	22	<15	2.13	6.158
T + 2 monthsa	1.51	1351	5.62	260	19	<23	2.81	6.291
T + 8 monthsb	1.50	1101	1.82	27	24	132	0.21	6.108

Time	Urine Na (mEq)	Urine K (mEq)	Urine Mg (mg)	Urine P (g)	Urine NH4 (mEq)	Urine Cl (mEq)	Urine Sulfate (mEq)	Urine Urea Nitrogen (g)	PCR
Time 0	105	64	47	0.955	56	88	<3	3.76	0.5
T + 2 monthsa	136	51	69	0.991	57	107	24	9.61	1.0
T + 8 monthsb	72	59	18	0.615	57	41	<4	4.52	0.6

Ca, calcium; CaOx, calcium oxalate; CaP, calcium phosphate; Cl, chloride; K, potassium; Mg, magnesium; Na, sodium; Ox, oxalate; P, phosphorus; SS, supersaturation calculated by EQUIL2; UA, uric acid; UUN = Urine urea nitrogen; PCR, protein catabolic rate.

^aReportedly on potassium citrate 10 mEq twice a day.

^bOn sodium bicarbonate 1300 mg twice a day.

Discussion

Here we have a patient with recurrent calcium phosphate stones. Urinary metabolic risk factors (Table 1) include low urine volume, hypocitraturia, and hypercalciuria. There are various forms of calcium phosphate stones. Brushite stones are uncommon because brushite is an early form of calcium phosphate that often transforms to carbonate apatite/hydroxyapatite or calcium oxalate over time.³ Hypocitraturia and carbonate apatite can be seen with urinary tract infections. Some laboratories report carbonate apatite and others attempt to quantify how much apatite is carbonated. It is important to know how your laboratory reports stone analyses in order to best interpret data regarding carbonate apatite. Our laboratory reports calcium carbonate and calcium apatite as distinct entities, and his stone composition had no carbonate component. Our patient did not report a history of urinary tract infections or active evidence of infection.

Reviewing his urine profile, our patient’s risk factors for calcium phosphate stone formation include low urine volume, hypercalciuria, and hypocitraturia, which are driving his urinary supersaturation (SS) of calcium salts. SS is a chemical concept where a solution contains more solutes than it should at a given temperature.⁴ Therefore, the solution has an increased propensity for crystallization. Urine SS takes into consideration the acid dissociation constant (pKa) of various urinary salts and the stability constant of all ion pairs. It can be calculated by a variety of methods. Although one could look at individual urinary parameters, reliance on urine values alone without consideration of SS may lead to overtreatment of individuals because various factors influence stone formation and growth risk.⁵ SS may also help determine stone type and guide therapy if a stone analysis is not available.^6,7 SS can be determined by multiple programs. EQUIL, later adapted to EQUIL2, is the most utilized computer program and incorporates additional urinary factors to better estimate SS, taking into account thermodynamic pressure for crystal, specifically hydroxyapatite, formation.⁸ Other programs to measure saturation risk include Joint Expert Speciation System, which includes additional urinary complexes; and Lithorisk, which graphically represents risk profiles.S1,S2 In the past, some researchers have advocated for the use of ion-activity products and activity product ratios, derived from concentration-to-product ratios, because computer-based calculations may overestimate true urine saturation; however, these calculations are not available in clinical practice, but are sometimes still used in research.S3-S4 Whichever method a clinician uses to determine stone risk, a host of urine parameters should be considered together to develop a clear picture of stone risk in the absence of continued stone formation.

Citrate is a known inhibitor of stone formation. It complexes with calcium in a 3:2 ratio to help inhibit crystal growth and aggregation.S6 Citrate is reabsorbed in the proximal tubule with sodium via the sodium dependent dicarboxylate transporter. Metabolic acidosis leads to increases in urinary citrate reabsorption and thus hypocitraturia, but it can also lead to hypercalciuria.S7–S10 In the setting of chronic metabolic acidosis, bone alkali stores help to buffer the plasma with concomitant loss of calcium, which can drive hypercalciuria. Metabolic acidosis also impacts renal handling of calcium. Normally calcium and sodium reabsorption are linked because the majority of calcium is reabsorbed paracellularly in the proximal tubule and thick ascending limb. The remaining less than 10% of calcium is reabsorbed in the distal convoluted tubule by an epithelial calcium channel called transient receptor potential vanilloid subgroup 5. In the distal convoluted tubule, transient receptor potential vanilloid subgroup 5 transcription and activity is impaired by the presence of acidosis, resulting in relative calciuria compared to urinary sodium. Alkali therapy can impact both urinary citrate and calcium through normalization of acidosis (Figure 1). In addition, citrate therapy in the presence or absence of metabolic acidosis has the added benefit of reducing hypercalciuria by chelating urinary calcium. This effect is specific to potassium citrate compared to other alkali salts.S11,S12

Figure 1.

Impact of alkali therapy on calciuria. (a) Restoration of bone resorption of calcium and bone buffers during metabolic acidosis. (b) In metabolic acidosis, despite increased sodium reabsorption, there is a relative hypercalciuria due to reduced activity and transcription of transient receptor potential vanilloid subgroup 5. Restoration of acidosis with alkali therapy restores the coupling of sodium and calcium reabsorption. (c) Urinary citrate can chelate urinary calcium and reduce calciuria.

NCC, sodium chloride cotransporter; NCX1, sodium calcium exchanger 1.

In calcium phosphate stone formers, because elevated urine pH is a risk factor for stone formation, there is concern that alkali therapy will further raise urine pH, which can preferentially lead to conversion of H₂PO₄^- (hydrogen diphosphate) to HPO₄ ^2- (hydrogen monophosphate) and drive calcium phosphate stone formation. Given that the dissociation constant (pKa₂) of phosphate is 6.8, many practitioners are cautious about raising the urine pH close to that level. Furthermore, in large reviews of repeat stone formers, when repeat stone analyses were completed, there was a trend to include more calcium phosphate composition over time.S9,S10 Those who transformed from calcium oxalate stone formers to calcium phosphate stone formers had a change in urine pH from 6.2 to 6.7.S10 Urine pH was a determining factor for transformation to calcium phosphate formation. However, upon closer review, although urine pH was a determining factor, the SS of calcium phosphate actually decreased from 1.9 to 1.6, indicating other factors were contributing to the risk of calcium phosphate stone formation.S10 It is important to point out, however, that these studies did not assess if patients received alkali therapy. When looking at patients with incomplete distal renal tubular acidosis (RTA) or medullary sponge kidney, conditions which are prone to calcium phosphate stone formation, use of potassium citrate improved hypocitraturia while increasing urine pH, but reduced hypercalciuria and overall stone recurrence.S13,S14 Interestingly, various studies of patients on stone-specific therapy show that urine citrate does not correlate with urine pH, even in patients receiving alkali therapy.S15,S16 This may be because there are mixed populations of patients with baseline abnormalities in urine citrate and urine pH that at baseline are not concordant. A more specific population would need to be studied to better characterize the impact of alkali therapy on urine citrate and urine pH.

There may be other benefits of citrate therapy in calcium phosphate stone formers. Citrate binds to calcium phosphate crystal surfaces to inhibit growth and aggregation through formation of calcium phosphocitrate complexes, a crystal growth inhibitor.S17 Citrate may also help to increase the level of Tamm-Horsfall protein (uromodulin), which is protective against crystal growth. Tamm-Horsfall protein is particularly important in preventing the development of calcium phosphate (hydroxyapatite) nephrocalcinosis.S18,S19 These data suggest that in calcium phosphate stone formers, alkali therapy may reduce stone formation through reduction of hypercalciuria or enhancement of other crystal growth inhibitors. These effects of citrate are not reflected as changes in SS. In summary, alkali therapy is not contraindicated in calcium phosphate stone formers and may help reduce hypercalciuria and increase crystal growth inhibitors.

Our patient started on sodium bicarbonate as he was unable to tolerate potassium citrate formulations. His gastritis and diarrhea improved, and he was encouraged to focus on increasing his water intake. Given his calcium phosphate stones, metabolic acidosis, and elevated urine pH, one would be tempted to consider distal RTA as a diagnosis. In fact, this patient’s urinary anion gap yields a positive value, which by traditional teaching is suggestive of a distal RTA. Fortunately, the clinical use of a urine anion gap to approximate urine ammonia is unnecessary, because the urinary level is measured for us here.S20,21 A review of reported dietary protein intake and urinary ammonia and sulfate offers clues to an alternative cause. Sulfates are a representation of dietary acid load. His high urine ammonia levels relative to his very low dietary acid load indicates gastrointestinal alkali loss and the excretion of a large acid load. Without the sulfate measurement, it is natural to be tempted to consider a distal RTA for this individual. Patients with a distal RTA will be unable to excrete acid via impaired ammoniagenesis and will have a negative discrepancy between urine ammonia and urine sulfate, where urine ammonia levels is notably lower than sulfate levels.S21 Whether his metabolic acidosis is due to diarrhea or RTA or both, his hypocitraturia is extreme and warrants therapy.

Metabolic evaluation (Table 1) after stent removal (T + 8 months) reveals hypokalemia with serum potassium 3.3 mEq/l, improved metabolic acidosis with serum bicarbonate of 21 mEq/l, and stable renal dysfunction. His urine profile was improved albeit still with hypocitraturia, and he had stable residual stone fragments on imaging. The increase in urine citrate excretion was not accompanied by an increase in urine pH. Although his urine citrate is still low, the improvement coupled with his modest urine volume contributes to a lower SS of both calcium salts decreasing his overall stone risk. Next steps for care include increasing alkali therapy as tolerated and normalization of potassium, which can help improve hypocitraturia, consideration of magnesium supplementation or reduction of his proton pump inhibitor if tolerated in order to improve urine magnesium levels (another inhibitor of stone formation), and further gastrointestinal evaluation.

For additional sources, see supplemental references.

Disclosure

The author declared no competing interests.

Patient Consent

The author declares that she has obtained consent from the patient discussed in the report.

Supplementary Material

Supplementary References