Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
Correspondence and offprint requests to: Ita P. Heilberg, MD, PhD, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina, R. Botucatu 740 CEP 04023-900, São Paulo, SP, Brazil.
Keywords: calcium; diet; medical treatment; nephrolithiasis; renal stones
Case report
A 42-year-old white man was referred to the outpatient renal stone clinic of the Division of Nephrology because of recurrent renal colic. The week before he had been rushed to the emergency room where he received pain relief drugs. On admission, the patient was asymptomatic, but reported that at age 32 he had passed his first stone. During the ensuing 10 years, he presented five other episodes of renal colic, and one endoscopic procedure was required for stone removal. The patient denied smoking and consumed alcohol occasionally. One brother has also passed stones. Physical examination was normal, his weight was 76 kg, height 167 cm, blood pressure 130/90 mmHg. A plain abdominal radiograph revealed one calcification probably located in the right ureter. A further intravenous pyelography revealed mild secondary calyceal dilatation. The patient was submitted to two sessions of extracorporeal shock wave lithotripsy (ESWL), being stone-free after the second one. Voided calculus fragments were not available for crystallographic analysis. Laboratory evaluation was started soon after stone removal, to determine underlying metabolic abnormalities. Serum concentrations of calcium, uric acid, phosphorus and creatinine were normal. Creatinine clearance was 113 ml/min. Urinalysis and urine culture were negative. Cystine screening was also negative. Two non-consecutive 24 h urine samples were obtained under conditions of usual diet. Urinary volumes were 4720 and 2570 ml/day. Urinary calcium excretion was high in both samples (373 and 285 mg/day respectively). Urinary sodium was also high (467 and 290 mEq/day). Urinary uric acid was within normal limits (665 and 624 mg/day) and citrate excretion was low in both samples (131 and 209 mg/day respectively). A 72-h dietary record showed a usual calcium intake of 314 mg/day, protein intake of 0.8 g/kg/day and phosphate intake of 673 mg/day. The estimated sodium chloride (NaCl) intake, calculated from Na excretion was 27 g/day. Dual X-ray absorptiometry showed that bone mineral density (BMD) was 1.020 g/cm2 (Z-score, -1.84; T-score, -1.48) in the lumbar spine, and 0.932 g/cm2 (Z-score, -1.15; T-score, -0.60) in the femoral neck. Serum intact parathyroid hormone was normal (29 pg/ml). Thyroid function tests and serum testosterone were normal. Potassium citrate (40 mEq/day) and thiazides (25 mg/day) were prescribed to control hypocitraturia, hypercalciuria and osteopenia, and the patient was advised to reduce NaCl intake, to maintain a calcium intake of approximately 800 mg/day and a daily fluid intake of at least 3000 ml. As the patient remained asymptomatic, he decided to discontinue potassium citrate. After 2 years on thiazides, there was a 5% increase in BMD in the lumbar spine (1.076 g/cm2) and an 11% increase in the neck site, and his urinary calcium decreased to 273 mg/day. A second dietary record showed that his calcium intake had increased to 719 mg/day, phosphate to 1288 mg/day, and protein to 1.2 g/kd/day (probably due to a higher consumption of dairy products). NaCl intake was decreased to 13 g/day. He remained stone-free until the fourth year of follow-up, when a routine ultrasound revealed two new stones (4 and 6 mm) in the right kidney. An abdominal plain X-ray was normal. The diagnosis of pure uric acid stones was made because the stones were radiolucent. Consequently the patient was advised to add potassium citrate to his thiazide regimen. An ultrasound performed 6 months later, showed only one stone, even though the patient had not reported passing any stone. Medication was maintained but one stone was observed at the time of the last control ultrasound. The patient is again asymptomatic, taking thiazides and potassium citrate.
On initial evaluation, this young man presenting with recurrent nephrolithiasis showed an increased urinary calcium excretion and sodium excretion, reduced urinary citrate and decreased bone mineral density. As primary hyperparathyroidism was ruled out, idiopathic hypercalciuria and a previous low calcium intake probably accounted for the osteopenia. A high sodium chloride intake, as evidenced by sodium excretion, probably contributed to an additional renal calcium loss. In a third determination of calcium excretion performed later on, with the patient instructed to avoid salt excess, hypercalciuria was still present although it was then of lesser magnitude. Concomitant dietary recommendations and drug treatment were suggested to the patient, who was supposed to increase his calcium intake and decrease his salt consumption. Thiazides and potassium citrate were prescribed, but only the former was taken during the first years of follow-up. His calcium excretion did not decrease as expected because of a higher calcium intake, and/or an insufficient thiazide dosage and/or a still high NaCl intake. On the other hand, his bone mineral density markedly improved. During follow-up, he formed new stones, of a possible pure uric acid composition. One of them was dissolved by potassium citrate and one remains.
Comment
This case illustrates some important aspects and difficulties in the management of renal stone disease. First, ESWL represents an important noninvasive tool to treat stones but the lithotriptor has no role in stone prevention. Second, it supports the notion that a long-term low-calcium diet does not prevent the recurrence of renal stones and might cause bone demineralization. Third, selective drug treatment should be effective, but the association of two or more drugs is sometimes a difficult goal to be achieved by the patients, mainly during periods when they are asymptomatic. It also stresses how difficult it is for the nephrologist, when facing a single case, to realize which of the measures have been truly effective for treatment.
I will discuss the last two aspects, focusing mainly on important modifications regarding the role of diet in the last decades.
The role of diet
Two observations highlight the association between dietary factors and stone formation. First, the `stone boom', which corresponds to the dramatic increase in stone disease incidence in western industrialized nations, after World War II, compared to the period during the war when malnutrition was the rule. Second, the `stone clinic effect', a phenomenon described by the Mayo Clinic years ago to explain the reduction of stone recurrence in 2/3 of the patients after basic dietary advice [1]. The role of many nutrients, like calcium, oxalate, sodium, potassium and protein has been investigated in the last years, because of their known effect upon urinary excretion as either promoters or inhibitors of stone formation.
Calcium
In the past, calcium restriction became a very popular recommendation based on the high incidence of hypercalciuria (around 50% [2]) in calcium stone forming patients, its impact on calcium oxalate and phosphate saturation [3], and also because of the contribution of calcium intake and intestinal calcium hyperabsorption to hypercalciuria. An acute oral calcium load test, described in 1975 by Pak et al. [4], was reported to clearly distinguish between absorptive and renal hypercalciuria. In a previous evaluation by our group [5], a 24-h urinary calcium excretion, under conditions of a mean usual calcium intake of 540 mg/day, was determined in CSF patients who previously presented an absorptive or renal response to this test. We observed that the majority of them, 63 and 78% of each group, presented normocalciuria rather than hypercalciuria. Since this apparently normal calcium excretion might have resulted from a combination of high calcium absorption and low calcium intake, those patients were then challenged to a higher calcium intake of 1500 mg/day given as supplement for 1 week. Regardless of whether there was a former absorptive or renal-like response to the acute load, the higher calcium intake disclosed the presence of subpopulations sensitive to calcium intake in previously normocalciuric patients [5]. Conversely, most of the hypercalciuric patients when challenged to a higher calcium intake did not present a further increase in their urinary calcium, showing that under conditions of low calcium intake, as it is the case for the Brazilian population [6], patients were already excreting calcium in excess of their intake, and therefore considered as dietary calcium-independent. In addition, as the morning urinary fasting calcium/creatinine (Ca:Cr) ratio seemed to be the single parameter which would distinguish between renal and absorptive hypercalciuric patients, with a cutoff value of 0.11, we repeated this determination in 31 patients [5], and found that 87% of them changed their results from values higher than 0.11 to lower values. Taken together, these data suggest that absorptive and renal hypercalciuria should be considered the same rather than two distinct entities, a hypothesis already raised by Coe et al. [3,7], representing two extremes of a continuum behaviour resulting from an abnormal regulation of 1,25 vitamin D. In a large prospective epidemiological study conducted by Curhan et al. [8], healthy men with different levels of calcium intake were followed-up for 8 years, and a surprising observation was made: the lower the calcium intake, the higher the incidence of stone formation. A hypothesis to explain this at first sight contraindicative relationship was that low calcium concentrates in the intestinal lumen caused a secondary increase in urinary oxalate due to decreased binding of oxalate to calcium within the gastrointestinal tract. Nevertheless, Bushinsky et al. [9], in an experimental model of genetic hypercalciuric rats fed increasing amounts of calcium in the diet observed a proportional increase in urinary calcium compared to the respective controls, but this was not accompanied by a parallel decrease in urinary oxalate. In CSF patients, the effects of increasing calcium intake from 500 to 1500 mg/day upon oxalate excretion have been recently evaluated by our group [10], and the preliminary results show a significant decrease of urinary oxalate in hypercalciuric but not in normocalciuric patients. Additional studies are still needed to further clarify whether the postulated relationship between colonic oxalate absorption and colonic load of calcium, is different in hypercalciuric versus normocalciuric subjects. Focusing on the bone issue, many investigators addressed the loss of bone mass in hypercalciuric patients [1117]. It was suggested that high animal protein and sodium intake are contributory factors [1216]. The authors also stressed the role of a low calcium diet in the genesis of such loss [1118]. But one has to keep in mind that calcium excretion is not solely affected by the intake of calcium, but that of other nutrients as well, such as animal protein, sodium, oxalate and potassium [12,19,20,21].
In summary, there are many reasons why calcium restriction should be avoided in hypercalciuric patients, as listed below.
Today more experts advise higher calcium intake. Although still hypothetical, this may even have additional advantages [22]. The substitution of meat protein by dairy product-derived protein will provide a higher intake of phosphate which co-precipitates with calcium in the intestinal lumen so that urinary phosphate does not increase; since calcium and magnesium compete for a common reabsorptive mechanism in the loop of Henle, increases in urinary calcium excretion are expected to induce an increase in urinary magnesium, a known inhibitor of crystal aggregation. Nevertheless, one has to consider that the benefits of a high calcium supply do not apply to calcium supplements, which usually are not taken with meals, hence losing their oxalate chelating properties [23].
Oxalate
Aside from primary and enteric hyperoxaluria, most cases found in CSF patients have `mild hyperoxaluria', defined by levels of urinary oxalate from 40 to 100 mg/day, with a reported frequency of 1263% [24]. Marangella et al. [25] have suggested that `mild hyperoxaluria' might be secondary to calcium hyperabsorption. The rational basis for oxalate restriction relies on the fact that calcium oxalate is the main component of most renal stones, and that there is a lower molar urinary oxalate concentration than calcium (Ca:Ox ratio is 5:1). This means that small changes in oxalate concentration have much larger effects on CaOx crystallyzation than large changes in calcium concentration. A recent experimental study by Bushinsky et al. [26] has shown that increases of dietary oxalate up to 2% during 18 weeks in hypercalciuric rats produced an elevation in oxalate excretion and a fall in urinary calcium excretion, probably due to oxalate binding intestinal calcium. In this model, since the higher urinary oxalate was offset by lower urinary calcium, the net effect was a decrease of CaOx saturation ratio. These results have raised the issue whether it is necessary at all to limit dietary oxalate intake in stone formers. In humans, only 1015% of urinary oxalate is derived from the diet [27]. Additionally, the ability of oxalate-rich food items to augment oxalate excretion depends not only on the oxalate content, but also on its bioavailability, its solubility and the form of salt in which it is present. Only spinach and rhubarb are considered to be high risk food items, for their high amounts of bioavailable oxalate [28]. Peanuts, instant tea, almonds, chocolate and pecans are considered as moderate risk food items [28]. Finally, the effect of dietary oxalate on urine oxalate critically depends upon calcium intake, since decreasing the calcium load in the intestinal lumen will increase the concentration of free oxalate anions available for absorption, as mentioned above. In healthy subjects, Hess et al. [22] have recently shown that the hyperoxaluria caused by a 20-fold increase in oxalate load can be totally prevented by a very high calcium intake of about 4 g/day. Accordingly, we are currently investigating whether this also holds true for smaller amounts of both nutrients in CSF patients (unpublished data). Preliminary results have shown no changes in oxalate or calcium excretion after a 2-fold increase in oxalate intake produced by consumption of one big milk chocolate bar per day containing 95 mg of oxalate and 430 mg of calcium for 3 days. Marshall et al. [29] have studied the effects of either oxalate or calcium restriction alone, as well as this concomitant restriction in stone forming patients and controls. In patients, oxalate restriction did not alter calcium excretion to a major extent and produced only a very minor decrease in urinary oxalate. CaOx activity was not altered much. On the other hand, a severe calcium restriction (down to 250 mg/day) caused an important elevation of urinary oxalate only when the supply of dietary oxalate was normal. The combined restriction of calcium and oxalate was the only way to prevent such an increase in urinary oxalate excretion, leading to an effective decrease of CaOx product activity far below the formation product [29]. Bataille et al. [30] evaluated the probability of stone formation after combined restriction of calcium and oxalate. He observed that the combined restriction was not able to decrease the probability of stone formation in dietary-independent hypercalciuria patients, in as much as a concomitant increase in oxalate excretion was still noted in these patients. In summary, the idea that a balance between calcium and oxalate intake must be maintained during meals is unquestionable. Long-term controlled studies are needed, however, to resolve whether one should recommend restriction of both items or recommend no restriction at all.
Protein
The nutrient that clearly has universal effects on most of the urinary parameters involved in stone formation is protein. High protein intake of animal origin contributes to hyperuricosuria due to the purine overload, to hyperoxaluria due to the higher oxalate synthesis and to hypocitraturia due to the higher tubular reabsorption of citrate [31,32]. Additionally, protein-induced hypercalciuria may be caused by higher bone resorption and lower tubular calcium reabsorption to buffer the acid load, and also by the elevated filtered load of calcium and by the presence of non-reabsorbable calcium sulfate in the tubular lumen [31]. An acute moderate protein restriction reduces urinary oxalate, phosphate, hydroxyproline, calcium, and uric acid and increases citrate excretion, as recently reported [33].
Potassium
An epidemiological study has reported that the lower the potassium intake, below 74 mmol/day, the higher the relative risk of stone formation [8]. Such an effect can be ascribed to an increase in urinary calcium and a decrease in urinary citrate excretion induced by a low potassium intake [21]. In a previous series studied in our laboratory [24], a low-normal potassium intake and a higher NaCl intake were observed in stone formers when compared to healthy subjects. The overall effect was a significantly higher urine Na/K ratio [34], increasing the risk for stone formation, as previously suggested by Cirillo et al. [35].
Sodium
The effect of sodium chloride (NaCl) intake on increasing calcium excretion is well established. Every 100 mmol increase in dietary sodium increases urinary calcium excretion by 25 mg [36]. The adverse effects of a high NaCl intake and the resultant higher calcium excretion have been well documented by many investigators [20,37,38]. In a previous analysis of our group [39], multiple regression suggested that a high NaCl intake (16 g/day), was the single variable that was predictive of risk of low bone mineral density in 85 CSF patients (odds ratio: 3.8) after adjustments for age, weight, body mass index, duration of stone disease, calcium and protein intakes and urinary calcium citrate and uric acid. Finally, a high NaCl intake is expected to lower citrate excretion as well [40].
Fluid intake
A high fluid intake is a very important goal to reduce urine supersaturation. A very well conducted 5-year randomized, prospective study [41] involving first stone episode patients has shown lower rates of recurrence (12%) in those with a higher intake of water compared to those without (27%). It should be emphasized that patients received no drug therapy and were not submitted to any dietary change so that the effect was exclusively explained by the selective increase in urinary volume [41]. To what extent the hardness and mineral composition of water affect stone risk remains controversial [4244]. As the calcium content of drinking water increases, calcium excretion increases, but oxalate excretion falls [43,45]. Water with a large amount of bicarbonate may increase citrate excretion [43] and magnesium content may favourably alter citrate and magnesium excretion [46]. Based on these findings, there is still no definite evidence that hard water, rich in calcium and magnesium, is more lithogenic than soft water. A very recent epidemiological study based on food-frequency questionnaires has examined the effects of particular beverages on the risk of symptomatic kidney stones in women [47]. Consumption of tea, caffeinated and decaffeinated coffee was associated with a reduction of risk of 810%, while wine decreased the risk by 59%. Conversely, grapefruit juice ingestion was associated with a 44% increased risk for stone formation. The authors speculated that the protective effects of coffee, tea and wine were caused by urinary dilution, determined by the ability of caffeine and alcohol to inhibit antidiuretic hormone. Therefore, the decreased risk for decaffeinated coffee might have been conferred by another mechanism. The adverse effects of grapefruit juice remained unexplained, since other citrus juices, such as orange and lemon, apparently prevent [48,49] and at least fail to stimulate stone formation because of their high citrate content. In summary, these results must still be interpreted with caution until adequate long-term randomized trials of dietary interventions are performed.
Vitamin C
The effect of large doses of vitamin C in increasing urinary oxalate excretion is controversial [50,51]. At least in part it may be a methodological artifact accounted for by the conversion of vitamin C to oxalate during the analytical procedure [51]. In a recent large epidemiological study, the intake of vitamin C was not associated with risk of kidney stones in women [52].
Therefore, the influence of diet on renal stone disease seems to be much more complex than thought in the past because multiple interactions take place between the different nutrients and thus variably influence urinary parameters. Dietary recommendation in renal stone disease can be summarized as shown in Table 1.
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Considering the high rate of recurrence of renal stone disease, there is no doubt about the need for medical preventive programmes. Nevertheless, further randomized, double-blind, placebo-controlled trials are required to validate the efficacy of such programmes. The paucity of drug trials can be ascribed to several factors [53]: (i) patient compliance is low because of the absence of symptoms between stone episodes; (ii) stone disease is heterogeneous and the course is unpredictable, requiring long treatment periods and a follow-up of at least 5 years to show any beneficial effect; (iii) a sufficient sample size is necessary to compare treated and untreated control patients; both groups must have a similar risk profile; (iv) the effect of a single drug has to be compared with placebo without associated dietary intervention which would be a potential confounder. Despite the potential merit of conservative treatment involving just diet and fluid intake modification, i.e. the so-called stone clinic effect [1], only fluid intake has been validated by a prospective study [41]. For ethical purposes, placebo groups of most trials generally receive diet and/or fluid recommendations.
Thiazide
Thiazides lower urine calcium resulting in a fall in calcium oxalate and calcium phosphate supersaturation. Two double-blind, randomized, prospective and placebo-controlled trials, one involving 25 patients given hydrochlorthiazide, 25 mg/day [54], and another involving 42 patients given chlorthalidone, 25 or 50 mg/day [55] documented a significantly lower rate of recurrence after 3 years (up to 25%) compared to placebo (up to 55%). Interestingly, these studies were performed in patients not categorized according to urinary lithogenic ions. The response to therapy was independent of baseline urinary biochemistry. We and others [56,57] have documented the additional benefits of thiazides on bone mass in small series. On the other hand, adverse effects (often dosage related) such as sexual impotence, potassium wasting, raised serum cholesterol and glucose tolerance, are reported in almost 23% of cases [55].
Allopurinol
Allopurinol blocks uric acid production, reducing heterogeneous nucleation of calcium oxalate by both uric acid and monosodium urate. In addition, uric acid and monosodium urate adsorb normally occurring macromolecular inhibitors of calcium oxalate crystallization. This stone promoting effect could be reversed by the administration of allopurinol. In the sole double-blind, placebo-controlled study involving 29 subjects receiving allopurinol 300 mg daily for 3 years, 51% had fewer recurrences than those treated with placebo [58]. Allopurinol has a low incidence of side effects, but the drug is effective in reducing stone recurrence only in calcium oxalate stone formers in whom hyperuricosuria is the only metabolic abnormality [59].
Potassium citrate
Potassium citrate reduces urinary saturation of calcium salts by complexing calcium and reducing ionic calcium concentration. Due to its alkalinizing effect, it also increases the dissociation of uric acid, lowers the amount of poorly soluble undissociated uric acid and reduces the propensity to form uric acid stones. The decrease of urinary calcium during the early period of treatment [49,60] represents a promising additional advantage of the drug. Potassium citrate is preferable to sodium citrate in the prevention of urolithiasis [60]. The former has been shown to decrease the stone formation rate in a randomized placebo-controlled study involving 18 patients with low citrate excretion who received 45 mEq/day of citrate for 3 years [61]. However, adverse effects of gastrointestinal origin including epigastric pain, abdominal distention or diarrhoea are common. Promising results with the use of newer citrate salts such as potassium-magnesium, not yet approved by the Food and Drug Administration, have also been shown in patients with idiopathic calcium oxalate nephrolithiasis [62] irrespective of baseline urinary biochemistry.
Other drugs
Potassium-acid phosphate [63] and magnesium hydroxide [55] were shown to have little or no effect on the prevention of stone formation. A neutral potassium phosphate preparation was shown to be better than placebo in reducing calcium excretion and raising urinary inhibitors of stone formation, hence inhibiting CaOx crystal agglomeration and spontaneous nucleation on brushite [64].
The latest evolution in the approach to calcium oxalate stone prevention is to abandon urinary metabolic profiling as a guide to prophylaxis both because this is time-consuming and expensive. Furthermore nonselective therapy is effective, as nicely reviewed recently [65]. The successful use of drugs in patients who have not been categorized according to different urinary derangements underlines the usefulness of such approach. Besides, in a given subject, the stone formation may not be due to one single abnormality. Overall, potassium citrate represents the most suitable drug for unselective treatment, because it is indicated for hypocitraturia, hypercalciuria, hyperuricosuria and renal tubular acidosis. On the other hand, identification of abnormal risk factors for urinary stones is still important to rule out secondary causes of nephrolithiasis, such as cystinuria, hyperoxaluria, renal tubular acidosis and infection stones. Among all of these examples, cystinuria, the most rare, represents the single entity for which specific therapy with tiopronin would be warranted, in addition to the need for alkalinizing therapy with potassium citrate as well. The dissolution of pure uric acid stones by potassium citrate also takes place during treatment, as suggested in the present case. The single contraindication to potassium citrate would be urinary tract infection because of the alkalinizing properties of the compound.
In conclusion, pain from renal colic provides the initial motivation to the patient to prevent a stone recurrence. Unfortunately when the symptoms subside, the compliance with dietary and pharmacologic regimens often becomes suboptimal. Well-designed, large, prospective epidemiological studies performed on healthy subjects have contradicted some long-held beliefs. Adequate long-term randomized trials with dietary interventions assessing stone recurrence and long-term measures of urinary composition as end-points, are difficult, but must nevertheless be performed.
References
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