Calcium phosphate stones
While kidney stones composed predominantly of calcium phosphate are less than 10 % of total stones, the importance of this compound arises from the recent findings that calcium phosphate appears to be an initiator of calcium oxalate stones.25 Randall plaque is an amorphous apatite that ruptures from its site of growth in the papillary interstitium through the papillary urothelium into the urinary space.25 Calcium oxalate then nucleates around the ruptured plaque and grows into a kidney stone.
Most calcium phosphate stones are reported by labs as hydroxyapatite, the same crystal phase seen in bone. Many of these stones probably start as brushite, a relatively unstable phase of calcium phosphate that may convert in vivo to hydroxyapatite. Urinary conditions that favor the formation of calcium phosphate stones are the combination of hypercalciuria and hypocitraturia in alkaline urine. At a higher pH, monobasic phosphate gives up a proton and becomes dibasic phosphate, which is more prone to combine with the divalent cation calcium and precipitate.
Patients with calcium phosphate stones should be evaluated for hyperparathyroidism and distal renal tubular acidosis (RTA). While incomplete RTA may also be a risk factor for calcium phosphate stones, testing for it has not been shown to lead to better results than if hypocitraturia is treated with citrate supplementation, regardless of the results of urine pH responses to acid loads.26 If the stone is composed of the calcium phosphate crystal phases carbonate apatite or struvite, urinary tract infection should be ruled out.
High quality clinical trials to address the prevention of calcium phosphate stones are lacking. Clinicians usually apply a similar preventive approach to treat calcium phosphate stones and calcium oxalate stones. The approach includes increased water intake to 3L per day, dietary changes and pharmacologic agents (Table 1). The recent finding that urinary calcium is highest after dinner and urine volume lowest during sleep (combining to yield significant nocturnal supersaturation) emphasizes the need for fluid intake at bedtime.27 This suggestion is not specific to stone composition.
The optimal diet for the prevention of calcium phosphate stones has not been established. Each patient should have 24-hour urinary collections with subsequent dietary modification targeted to specific issues. Perhaps most important for calcium phosphate stones, a decrease in dietary sodium intake is associated with reduction of urinary calcium excretion. Decreased animal protein consumption leads to increased urinary citrate.
Adherents of the DASH (Dietary Approaches to Stop Hypertension) diet have fewer stones and the effect might apply to calcium phosphate stones, though the diet has never been assigned to test its efficacy for that purpose.28 Higher calcium diets have not been studied for calcium phosphate stones specifically. Therefore, patients who form calcium phosphate stones are recommended a low salt, moderate animal-protein diet.
Pharmacologic therapy should be guided by the findings of the 24-hour urine collection. Controversy arises regarding citrate supplementation.29 Citrate is an inhibitor of calcium stone formation, whether oxalate or phosphate, but its metabolism causes consumption of a proton and alkalinization of the urine.
The increased urine pH increases the supersaturation of calcium phosphate and potentially promotes calcium phosphate stones. However, it is not inevitable stones will recur if patients increase their fluid intake, experience a small decrease in urinary calcium due to the effects of alkali on bones and renal calcium transport, and have increased urinary citrate excretion.
The net effect of citrate supplementation in calcium phosphate stone formers has not been studied, although non-randomized studies claim benefit in patients with RTA.30 Potassium citrate is preferred over sodium citrate to decrease the effect of sodium on calcium excretion. The role of thiazides in calcium oxalate stones has been well established, but none of the studies specifically examined calcium phosphate stone formers. Nonetheless, treating calcium phosphate stone formers with thiazides makes sense and may allay worries about citrate use, especially if urine calcium falls in response to the effects of alkali on bone turnover and renal calcium reabsorption.
Uric acid stones
The most prevalent urinary abnormality causing uric acid stones is low urine pH.31 Uric acid is a weak organic acid with pKa 5.35 at 370C. In acidic urine, its solubility decreases dramatically. The urine then becomes supersaturated with uric acid and stones result. At urine pH 5.3, uric acid solubility is 200 mg/L; at a pH of 6.5 more than 1,200 mg/L of uric acid can be present without reaching supersaturation. The majority of patients with idiopathic uric acid stones have normal uric acid excretion with low urine pH.
The etiology of “unduly acidic urine” is not completely understood. Recent epidemiologic, metabolic, and physiologic studies have linked insulin resistance to low urinary pH. Urine pH is inversely correlated with BMI and insulin resistance.32,33 Insulin stimulates ammoniagenesis in renal tubular cells and sodium/hydrogen exchange in the proximal tubule. The insulin resistance then impairs ammoniagenesis resulting in excessive unbuffered protons in the distal tubule and a low urine pH. There is also evidence that patients with metabolic syndrome have increased net acid excretion, further contributing to a more acidic urine.34
Urinary alkalinization is the mainstay of treatment for patients with uric acid stones with or without hyperuricosuria. There are no RCTs evaluating the efficacy of treatment, but the effects are so obvious in practice that RCTs seem superfluous. Urinary alkalinization with potassium citrate is usually used as first-line treatment of uric acid stones. The xanthine oxidoreductase inhibitors allopurinol and febuxostat are unlikely to offer benefit if urine pH is not increased and are reserved for patients who have stones despite adequate alkalinization or are difficult to alkalinize such as those with bowel disease. The starting dose of potassium citrate is from 20-40 meq per day in divided doses. The goal is to keep urine pH greater than 6.0. Urine pH testing can be useful; we ask patients to measure urine pH once a day at varying times. Inexpensive pH testing paper can be obtained from Microessential Laboratory (Available at https://www .microessentiallab.com, item #067). In case of reduced glomerular filtration rate or hyperkalemia, sodium citrate or bicarbonate are reasonable alternatives. After stones are removed or dissolved, either of these compounds taken once daily, usually after dinner or at bedtime, may suffice for uric acid stone prevention.35 There are no data regarding the optimal dosing and frequency of alkali administration.
Kidney stone prevention is often neglected, and deserves more attention by nephrologists and urologists. Adequate and quantitative counseling regarding fluid intake is the first step and is effective and inexpensive. Appropriate dietary manipulations can be prescribed based on 24-hour urine collections. While dietary adherence may be difficult for many patients to achieve, medical therapies are effective and underutilized.
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