Orthophosphates

Abstract

Hypercalciuria is the commonest metabolic alteration found in patients with idiopathic calcium disease, and the absorptive type is the most prevalent. Therapies for hypercalciuria include thiazides, thiazide-like drugs, alone or together with potassium citrate, and bisphosphonates. In the past, orthophosphates appeared to be highly indicated for absorptive hypercalciuria treatment since they reduce serum 1,25-dihydroxyvitamin D levels, urinary calcium excretion, and, perhaps, bone resorption. Inorganic phosphate salts include acid potassium phosphate, neutral mixtures of acid and alkaline potassium phosphate, and neutral mixtures of sodium and potassium phosphate. Moreover, neutral potassium orthophosphates include compounds characterized by fast or slow release. The effect is most pronounced for neutral orthophosphates, which not only reduce calcium and increase pyrophosphate excretion but also induce greater urinary citrate excretion; inhibitory power in urine against the crystallization process thus results as increased. The hypocalciuric response to the drug is probably the result of the combined effects of reduced intestinal calcium absorption, increased renal tubular calcium reabsorption, and diminished bone resorption. Positive effects of orthophosphate therapy have been described in several papers, although most of them consisted of open non-randomized studies. There are only two double-blind studies with orthophosphate treatment; in the first, no differences were observed between treated and untreated patients, whereas in the second, a reduced rate of stone formation was observed.

Common side effects of orthophosphate therapy include diarrhea, abdominal cramps, nausea, and vomiting. According to the type of orthophosphate, other side effects have been reported. Furthermore, alkaline phosphates promote dissociation of urinary phosphate and increase brushite saturation. In conclusion, orthophosphates have been proposed as an alternative for treating patients with hypercalciuria, especially of the absorptive type, but there are insufficient studies, above all clinical randomized trials, to confirm their efficacy beyond any shadow of a doubt. Their usefulness may thus be limited to being a second choice for the treatment of selected patients. In accordance with these indications, no mention of orthophosphates is reported for hypercalciuria treatment in the most recent guidelines on urolithiasis.

Introduction

Idiopathic calcium stone disease is a common event in clinical practice, and kidney stones have shown a progressive increase worldwide, with a prevalence ranging between 2 and 20% [1]. Kidney stone disease shows a high recurrence as its main trait, but the number of patients undergoing metabolic evaluation is very scarce, although metabolic evaluation allows the identifications of about 97% of metabolic risk factors for stone formation [2]. Selective medical treatment appears to be an important tool in clinical prophylaxis and treatment of renal stone disease; in fact, surgical treatment such as extracorporeal shock-wave lithotripsy does not treat the underlying cause of stones and thus does not induce a decrease of recurrence. About 40% of patients presenting a first episode of kidney stones show a recurrence within 3 years if adequate prophylactic and medical treatment are not established. The positive effects of medical treatment pointed out by several authors [2–6] have been further confirmed by Parks and Coe [7], who observed that patients who were actively treated showed a significant decrease in stone recurrence and urological procedure rates. Several risk factors may induce the formation of kidney stones, which are mainly composed of calcium oxalate or calcium phosphate; hypercalciuria is the commonest metabolic alteration found in patients with idiopathic calcium disease [8–11], and its percentage is different according to the type of hypercalciuria as well as to whether hypercalciuria occurs singly or combined with other metabolic alterations. Hypercalciuria may favor stone formation by increasing the urinary saturation of calcium oxalate and calcium phosphate as well as by reducing inhibitor activity in urine by binding negatively charged inhibitors and inactivating them [8, 10]. At the moment the diagnostic tests for evaluating hypercalciuria types (absorptive, renal, resorptive, hypercalciuria linked to phosphate renal tubular leak) are not considered ­cost-effective; but, very recently, Pak et al. have suggested a very simple method for absorptive hypercalciuria diagnosis based on the documentation of high 24-h urinary calcium excretion on both free and restricted diets [12]. Several studies have indicated that in most patients hypercalciuria is due to an inappropriately increased intestinal absorption and that absorptive hypercalciuria is the commonest type [8, 13, 14]. Absorptive hypercalciuria is characterized by normocalcemia alongside hypercalciuria, normal to low levels of parathyroid hormone (PTH), and normal to high serum concentrations of 1,25-­dihydroxyvitamin D [15, 16]. An excessive bone loss due to increased cytokine levels may contribute to hypercalciuria pathogenesis [17]. In these patients bone loss seems to influence mainly trabecular bone [18]. The pathogenetic aspects of absorptive hypercalciuria are not yet completely understood, although some authors have found an increased plasma level of 1,25-dihydroxyvitamin D in a large number of these patients [14–16]. An increased number of vitamin D receptors and/or sensitivity to them have also been proposed [14]. Other authors have suggested that the main alteration in patients with absorptive hypercalciuria may be a primary phosphate renal tubular leak inducing an increase of 1,25-dihydroxyvitamin D production and thus hypercalciuria [19]. Lau et al. [20] have shown that phosphate infusion in rats increases calcium reabsorption in the distal convoluted tubule, and possibly in the terminal part of the nephron independently of PTH, plasma calcium concentration, and renal handling of sodium. The authors’ data suggest that these effects may be mediated by an increase in tubular fluid and/or plasma phosphate concentration. The commonest therapies for the treatment of hypercalciuria include thiazides or thiazide-like (indapamide) drugs, alone or in association with potassium citrate. In the past, of the drugs used in hypercalciuria treatment, orthophosphates have appeared to be the most indicated for idiopathic absorptive hypercalciuria treatment, above all when hypophosphatemia is present. Orthophosphates have also been proposed for resorptive hypercalciuria treatment and other conditions associated with renal stone formation (primary hyperoxaluria, type I renal tubular acidosis, sarcoidosis, immobilization, carbonic anhydrase inhibitor-induced stones). Orthophosphates have been widely used for the treatment of idiopathic calcium stone formers [21–27] as they induce both a decrease in urinary calcium excretion [20–24] and an increase in inorganic pyrophosphates [22, 25], which are among the most powerful urinary inhibitors of calcium crystal formation and aggregation [21, 22, 25].

Mechanism of Action

Urinary calcium decrease may be induced by several mechanisms.

First, orthophosphate may reduce intestinal calcium absorption by means of physiochemical binding of calcium by phosphate in the intestinal tract and by a decrease in 1,25-dihydroxyvitamin D₃ synthesis. Some authors have proved that orthophosphate therapy lowers plasma 1,25-dihydroxyvitamin D₃ concentration in patients with hypercalciuria [19].

Second, orthophosphate induces an increase in plasma phosphate and a contemporary decrease in plasma calcium concentration, which induces PTH secretion [28]. In turn, the PTH increase induces both a decrease in glomerular filtration rate and an increase in tubular calcium reabsorption with a consequent decrease in urinary calcium excretion. Otherwise, orthophosphates could, through a plasma phosphate concentration increase, induce an inhibition of 1,25-dihydroxyvitamin D₃ synthesis, thus reducing intestinal calcium absorption. Lau and Eby [29] have shown that phosphate infusion in rats increases calcium reabsorption in the distal convoluted tubule, and possibly in the terminal part of the nephron independently of PTH, plasma calcium concentration, and renal handling of sodium. The authors’ data suggest that these effects may be mediated by an increase in tubular fluid and/or plasma phosphate concentration.

Third, orthophosphates may contribute to reducing urinary calcium excretion by decreasing bone resorption [26, 30]. Inorganic phosphate salts include the following: acid potassium phosphate (KH₂PO₄), a neutral mixture of acid and alkaline potassium phosphate (KH₂PO₄  +  K₂HPO₄), and a neutral (pH 7) mixture of sodium and potassium phosphate (Na₂HPO₄  +  KH₂PO₄) [31].

Differential Absorption from Available Preparations

Moreover, neutral potassium orthophosphates include compounds characterized by a fast or slow release [32]. Slow-release neutral-K-phosphate composition includes a mixture of mono-dibasic phosphate salts of potassium and does not contain sodium; this phosphate composition, maintaining a urinary pH of 7.0, avoids the problems linked to acidic or alkaline phosphates. The positive changes observed in urine chemistry include a decrease in calcium urinary excretion together with an increase in phosphate, potassium, citrate, and pyrophosphate; moreover, a decrease was observed in calcium-oxalate urinary saturation, brushite spontaneous nucleation, and calcium-oxalate crystal agglomeration [32]. In the plasma, a decrease of 1,25-dihydroxyvitamin D₃, alkaline phosphatase, and procollagen concentration was observed. The restricted phosphate release limits the high phosphate concentration in bowel lumen observed with rapid-release orthophosphates. Table 91.1 summarizes the therapeutic effects of slow- and rapid-release orthophosphates. From a theoretical point of view, neutral phosphates seem to be safer than acid phosphates, which induce a greater production of fixed acid that in turn increase rather than decrease urinary calcium excretion [33, 34]. Nevertheless, there is no general agreement about the therapeutical response to this treatment [21–27, 33]. Several authors (Table 91.2) have shown positive effects for orthophosphate therapy, although most of these papers consisted of open ­non-randomized studies with patients having different types of stone ­disease with nonhomogeneous criteria used for their enrolment. Furthermore, the authors describe several aspects of orthophosphate therapy such as plasma and urinary laboratory modifications, side effects, remission rates, and modifications in stone formation rate (Table 91.3). These contrasting results seem to be explained by the paper of Lau et al. [31] from 1979 detailing randomized studies of patients with hypercalciuria to compare the acute and chronic effects of acid phosphate and neutral phosphate on the excretion of stone-forming salts.

Table 91.1 Therapeutic effects of orthophosphates

Table 91.2 Positive effects of orthophosphate therapy

Table 91.3 Reported stone episode rates before and during treatment with orthophosphate

Dosage

One gram of acid phosphate contains 9 mEq of potassium and 23 mEq of sodium as the monobasic salt; 1 g of neutral phosphate contains 28 mEq of sodium and 28 mEq of potassium, present as monobasic and dibasic forms of phosphate (dibasic to monobasic ratio 3:1; pH 7.3). The difference in the amount of fixed base (56–32  =  24 mEq) represents the hydrogen ion load per gram of elemental phosphorus that must be buffered and excreted when using the acid phosphate preparation. Lau et al. [31] proved that both acute and chronic acid and neutral phosphate treatment induce different effects on the excretion of some risk factors for stone formation. In fact, urinary calcium excretion was significantly higher during acid phosphate treatment, associated with an increased net acid excretion (titratable acid, ammonium, and net acid excretion). These results give a clear physiological explanation of the reduced action of acid phosphate treatment in decreasing calcium urinary excretion, whether in normocalciuric subjects [26, 35] or in hypercalciuric stone formers [36–37]. Moreover, Lau et al. [31] have shown that both acid and neutral phosphates induce a decrease in urinary calcium excretion, but the amount of calcium decrease obtained with acid phosphate was sim ilar to that induced by dietary calcium restriction. These data are in agreement with the clinical observation that acid phosphate showed the same efficacy as dietary calcium restriction in producing stone disease remission [33]. A possible explanation for the different results after phosphate treatment described in the literature [22, 24, 26, 27, 30] may be found in the quantity of hydrogen ions present in the acid phosphate rather than in the slight difference in dosages [31]. Furthermore, the 64 mmol of acid phosphate ingested daily by the patients may produce 48 mEq of hydrogen ions, a sufficient amount to induce a decrease in urinary citrate excretion [31]. Both acid and neutral phosphates induce a similar phyrophosphate urinary excretion [31]. Finally, the relative urinary supersaturation was only decreased by neutral phosphate [31, 38]. Taken together, these results indicate that neutral salts may be preferred for stone formers with idiopathic hypercalciuria. Positive effects of orthophosphate therapy have been described in several papers (see Table 91.2), although most of them consisted of open non-randomized studies including patients with different enrollment and treatment criteria (types of stones, presence/absence of hypercalciuria, male/female ratio, acidic or neutral orthophosphate, drug dosage). In all the literature, there are only two double-blind studies with orthophosphate; in the first, no significant differences were observed between treated and untreated stone formers undergoing therapy with rapid-release orthophosphate [33]. The second study, testing a slow-release orthophosphate, showed a reduced rate of stone formation [32]. Orthophosphate preparations have a potential use in absorptive hypercalciuria since they reduce serum 1,25-dihydroxyvitamin D levels, urinary calcium excretion, and perhaps bone resorption. Absorptive hypercalciuric patients with hypophosphatemia should be particularly responsive. Unfortunately, the use of available preparations of rapid-release phosphate is often limited by the need for frequent dosing, as well as by gastrointestinal symptoms such as abdominal cramping and diarrhea. The only controlled trial using phosphate showed no benefit, but the acidic and sodium-containing forms of phosphate used in the trial may be expected to be less effective due to the potential hypercalciuric and hypocitraturic effects of the accompanying acid and sodium load [33]. The hypocalciuric response to the drug is probably the result of the combined effects of reduced intestinal calcium absorption, increased renal tubular calcium reabsorption, and diminished bone resorption. The decline in calcium intestinal absorption is in agreement with the reduction in serum 1,25-dihydroxyvitamin D₃. Renal calcium reabsorption is probably due either to PTH increase or the direct action of phosphate on the renal tubule. Decreased alkaline phosphatase and fasting urine calcium suggest that bone turnover was reduced by the treatment. Decreased skeletal resorption is to be expected since phosphate has been demonstrated in vitro to reduce bone resorption [48]. The absence of age-related bone loss over 4 years in hypercalciuric patients provides supportive evidence that calcium loss from bone may have diminished with treatment [24].

Side Effects of Orthophosphates

Finally, common side effects of orthophosphate therapy include diarrhea, abdominal cramps, nausea, and vomiting. According to the type of orthophosphate, other side effects have been reported: for example, the acidic and ­sodium-containing forms of phosphate used in some studies may be responsible for hypertension and may be expected to be less effective due to the potential hypercalciuric and hypocitraturic effects of the accompanying acid and sodium load. Furthermore, alkaline phosphates promote dissociation of urinary phosphate and increase brushite saturation. Possible effects on parathyroid hormone and metastatic calcifications are also reported.

Conclusion

In conclusion, orthophosphates have been proposed as an alternative for treating patients with hypercalciuria, especially of the absorptive type, but as debated by the members of the Advisory Board of European Urolithiasis Research (ABEUR) during the consensus conference organized in Mannheim on 23 January 1999, there are insufficient studies, above all clinical randomized trials, to confirm their efficacy beyond any shadow of a doubt. Their usefulness may thus be limited to being a second choice for the treatment of selected patients [49]. In accordance with these indications, over recent years the use of orthophosphates in hypercalciuria treatment has declined progressively, and no mention of them is reported in the most recent guidelines on urolithiasis [50].