Introduction
Because recurrence rates in calcium oxalate stone formers may reach 50% within 10 years [
1], prophylactic measures are indicated. They include either clinical observation and immediate urological treatment of recurrences, or comprehensive metabolic evaluation and preventive treatment [
2]. The latter consists of dietary advice and/or medication. For many years, our daily clinical approach in idiopathic calcium oxalate stone formers has been to reduce urinary supersaturation primarily by dietary advice (DA) alone, based on explanations of stone forming mechanisms and individual dietary preferences of patients [
3].
The ultimate goal of any DA should be to reduce urinary supersaturation, the driving force for stone formation [
4]. Indeed, Prochaska et al. [
5] have recently demonstrated in large cohorts that the likelihood of becoming a stone former increases almost linearly with increasing calcium oxalate supersaturations (CaOx-SS), both in women and in men. Although dietary effects on overall stone risk are mentioned in many guidelines and review articles, only few prospectively controlled investigations have addressed the direct effect of dietary modifications alone (without medication) on urine supersaturations [
6‐
9]. Only one short 7-day study [
6], taking into account multiple dietary factors according to the Guidelines of the European Association of Urology [
10], achieved significant reductions in urinary supersaturations of calcium oxalate as well as brushite and uric acid, measured by EQUIL 2 [
11]. Two other, more extended studies applied either a DASH-style diet (high in fruit, vegetables, whole grains and low-fat dairy products, low in saturated fat, total fat, cholesterol, refined grains, sweets and meat) [
7] or diets low in animal protein vs. high in fiber [
8]. Overall, all these protocols were not able to significantly lower urinary CaOx-SS [
7,
8].
Our own study in idiopathic calcium stone formers [
9], using EQUIL 2 for supersaturation calculations [
11], had a mean follow-up of 5 months and compared CaOx-SS before and after advice for a “common sense diet”. The advice aimed at high urine volume (> 2000 ml/day), lower daily meat protein (about 1 g/kg body weight) and lower sodium intake (24-h urine sodium < 200 mmol/day) as well as daily consumption of 800 mg calcium from dairy products. Overall, CaOx-SS remained unchanged on the recommended diet. Interestingly, individual diet-induced increases in CaOx-SS were strongly positively related to increases in urinary oxalate, but not to rises in urinary calcium [
9]. On the other hand, CaOx-SS significantly decreased with increases in urine volume, urine pH, and gastrointestinal alkali intake [
9]. This is in accordance with Robertson [
4] who described low urine volumes, high urinary oxalate and lack of urinary citrate (alkali) as major drivers of CaOx-SS and crystallization.
Whereas increasing urine volume has emerged as a logic prophylactic measure for lowering urine supersaturation, it is still not entirely clear how the important reduction in urinary oxalate is best achieved. Many physicians still recommend a diet low in oxalate. However, as summarized by Robertson [
4], there is to date no evidence from controlled trials that decreasing oxalate intake has a beneficial effect on stone recurrences. Moreover, physical chemistry predicts that even small increases in urinary oxalate are much more dangerous for CaOx-SS than rises in urinary calcium [
12], because there is always a considerable molar excess of calcium present in urine (for instance, from nutrition and bone metabolism), whereas calcium oxalate crystallization occurs in a 1:1 molar ratio. Thus, small increases in urinary oxalate, for instance, after oxalate-containing snacks, will immediately promote calcium oxalate crystallization, because of the excess calcium ions available for crystallizing with oxalate in urine. On this background, we have demonstrated in humans that the severe hyperoxaluria occurring after ingestion of a 20-fold amount of oxalate can be abolished by simultaneous ingestion of large amounts of calcium from natural sources [
13]. This allows calcium oxalate precipitation already in the intestinal tract, whereby enteric absorption and urinary excretion of oxalate are reduced [
13]. Finally, reducing animal protein consumption (meat, fish, poultry) and increasing intake of alkali (vegetables, salad, fruit) reduce hyperacidity and raise urinary citrate, a chelator of calcium ions [
14]. These changes reduce urinary CaOx-SS as driving force for stone formation [
4,
14,
15].
In the present study, we tested the effects of a simple DA on 24-urinary chemistries and CaOx-SS in truly idiopathic calcium oxalate stone formers (ICSF). Our DA primarily addresses five parameters which appear pathophysiologically most relevant to CaOx supersaturation and stone formation, namely urine volume, calcium (U-Ca) and oxalate (U-Ox) as well as uric acid (U-UA, marker of “acid”, i.e., animal protein) and citrate (U-Cit, marker of alkali). Changes in urine chemistries were expressed by a simple, retrospectively assigned adherence score in every single ICSF, and alterations in CaOx-SS were correlated with changes in urine chemistries as well as with the adherence scores.
Discussion
The most relevant finding of this study is that simple DA, if followed consequently, can reduce urinary CaOx-SS in ICSF under everyday practical conditions. Our advice comes close to what has been named empiric dietary therapy [
23]. We addressed five easily measurable urine parameters, i.e., (1) increasing urine volume by increasing fluid intake, (2) reducing U-Ox by increasing calcium intake to not more than 1200 mg/day [
20] simultaneously with all meals/snacks, whereby (3) U-Ca is expected to rise. Furthermore, we advised on (4) reducing “acid” intake (meat protein) and thereby U-UA as well as (5) increasing alkali consumption (vegetables/salad/fruit) and thereby U-Cit. Overall, our intervention changed all five urine parameters in the intended direction. This was accompanied by a 21.5% reduction in CaOx-SS.
As already demonstrated in another group of calcium stone formers under everyday conditions [
9], increases in U-Ox and reductions in urine volume emerged as the most important determinants of a rise in CaOx-SS. On the other hand, CaOx-SS in the present study fell despite a significant 47% increase in calcium excretion, and changes in CaOx-SS after DA were not at all correlated to changes in U-Ca. This is again in complete accordance with our previous supersaturation calculations [
9], using EQUIL 2 [
11]. For many years, there has been a debate about the relative effects of U-Ca and U-Ox on urinary CaOx-SS. Based on physico-chemical principles, Robertson et al. [
12] have convincingly demonstrated years ago that CaOx-SS in urines exponentially rises with U-Ox concentrations over the full concentration range occurring in humans, i.e., up to 0.7 mmol/L. On the other hand, CaOx-SS plateaus if U-Ca concentrations rise above 5 mmol/L even beyond the normal range, i.e., up to 15 mmol/L [
12]. Opposite to these results, Pak et al. [
24] have provided evidence that increasing urinary concentrations of both calcium and oxalate exert similar effects on urinary CaOx-SS. However, their calculations were performed only at the lower urinary concentration ranges of calcium (up to 7.5 mmol/L) as well as oxalate (0.46 mmol/L) [
24], Fig.
1, values that could be exceeded at least transiently in human beings. Indeed, the ingestion of 50–100 g of chocolate can induce urinary oxalate excretion rates to reach values usually found in cases with primary hyperoxaluria [
25]. Altogether, these findings emphasize the crucial role of increases in U-Ox for urinary CaOx-SS, whereas U-Ca is rather of negligible importance in contributing to CaOx-SS under everyday practical conditions.
Our strategy to reduce intestinal oxalate absorption by simultaneously ingesting calcium with all meals/snacks and thereby avoiding increases in U-Ox is based on previous investigations by ourselves [
13], mentioned above, as well as by others [
26,
27]. When calcium carbonate was administered as a supplement, either 1 g with every meal or 3 g in one dose at bedtime, to healthy volunteers on a controlled diet, calciuria rose to a similar extent under both conditions in comparison with baseline values [
26]. However, urinary oxalate excretion as well as CaOx-SS, determined by Tiselius’ index as in our study, only increased when calcium supplements were taken separately from meals at bedtime, whereas it fell significantly when calcium supplements were taken simultaneously with meals [
26], as in the present study. Presumably, ingestion of calcium supplements with meals reduced oxalate absorption and thereby abolished subsequent rises in U-Ox [
26]. Indeed, in a tightly controlled study, Holmes et al. [
27] had demonstrated that urinary oxalate excretion was determined by the oxalate/calcium ratio in the diet: both an increase in oxalate consumption at stable calcium intake as well as a reduction in calcium intake at stable oxalate consumption raised urinary oxalate excretion, indicating that the amount of dietary calcium in relation to the amount of ingested oxalate affects the intestinal bioavailability of oxalate [
27].
It is well known that an exaggerated animal protein intake (meat, fish, poultry) is associated with increases in U-Ca, U-Ox and U-UA, whereas decreases in U-Cit and urine pH are observed [
4]. Our advice, aiming at an improved equilibrium between “acid”—only one daily serving of animal protein—and “alkali”—at least three daily servings of vegetables/salad/fruit—was able to significantly reduce U-UA (marker of “acid”) and tendentially increase U-Cit (marker of “alkali”). As explained above (see results), the latter was due to the fact that the overall protein intake, i.e., animal as well as dairy protein, was unchanged, when assessed by urinary urea excretion, because we had advised to increase calcium intake also from dairy products, which carries an extra acid load from dairy protein [
22].
An advantage of our approach is that the maximum adherence score of + 5, i.e., changes of all five relevant urine parameters (volume, U-Ca, U-Ox, U-UA and U-Cit) in the intended direction, predicted a reduction in CaOx-SS in 100% of cases (see Fig.
3). If confirmed in higher numbers of ICSF, the use of this easily derived adherence score could be a clinical surrogate for more sophisticated supersaturation calculations in the future.
The study has some limitations: first of all, the individualized DA, although based on simple principles, is relatively time consuming to perform and might, therefore, not be suited to any kind of stone clinic, for instance in situations with time restrictions due to heavy patient load. In addition, motivating patients again and again to re-adapt their diet and collect control urines several times until they reach a satisfactory result may not always be easy. Second, a single 24-h urine as a control of good adherence to DA may be insufficient. Indeed, our previous study has demonstrated that self-declared good adherence to dietary and lifestyle measures (100% adherence on 6–7 weekdays) was only reported by 26.1% of stone formers after 3 months [
3]. Thus, dietary patterns may differ from day to day and—at least in some patients—only be “ideal” during stone clinic-ordered 24-h control urine collections. Third, the strategy is not generalizable and for instance would have to be thoroughly tested in a cohort of the increasingly common calcium oxalate monohydrate stone formers with enteric hyperoxaluria after bariatric surgery [
28]. And last but not least, reducing supersaturation within 3–4 months after DA does not automatically imply a long-term reduction in stone recurrence rate.
In conclusion, our simple DA addressing an increased fluid intake, raising calcium consumption with all nutrients to reduce intestinal oxalate absorption, and balancing the acid–base content of the diet can reduce urinary CaOx-SS in ICSF by 21.5%. We provide again evidence that CaOx-SS in urine as driving force for calcium oxalate stone formation is primarily driven by increases in U-Ox and decreases in urine volume, but not by the extent of calciuria. By considering changes of five 24-h urine parameters after dietary advice—volume, U-Ca, U-Ox, U-UA and U-Cit—a simple adherence score can be calculated which significantly correlates with alterations in CaOx-SS. In the future, this might help physicians to evaluate adherence to dietary advice and to individually tailor recommendations to idiopathic calcium stone formers, especially in settings where supersaturation calculations are not routinely obtained.
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