Dietary interventions for preventing complications in idiopathic hypercalciuria

  • Review
  • Intervention

Authors


Abstract

Background

Idiopathic hypercalciuria is an inherited metabolic abnormality that is characterised by excessive amounts of calcium excreted in the urine by people whose calcium serum levels are normal. Morbidity associated with idiopathic hypercalciuria is chiefly related to kidney stone disease and bone demineralisation leading to osteopenia and osteoporosis. Idiopathic hypercalciuria contributes to kidney stone disease at all life stages; people with the condition are prone to developing oxalate and calcium phosphate kidney stones. In some cases, crystallised calcium can be deposited in the renal interstitium, causing increased calcium levels in the kidneys. In children, idiopathic hypercalciuria can cause a range of comorbidities including recurrent macroscopic or microscopic haematuria, frequency dysuria syndrome, urinary tract infections and abdominal and lumbar pain. Various dietary interventions have been described that aim to decrease urinary calcium levels or urinary crystallisation.

Objectives

Our objectives were to assess the efficacy, effectiveness and safety of dietary interventions for preventing complications in idiopathic hypercalciuria (urolithiasis and osteopenia) in adults and children, and to assess the benefits of dietary interventions in decreasing urological symptomatology in children with idiopathic hypercalciuria.

Search methods

We searched the Cochrane Renal Group's Specialised Register (23 April 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE.

Selection criteria

We included all randomised controlled trials (RCTs) and quasi-RCTs that investigated dietary interventions aimed at preventing complications of idiopathic hypercalciuria, compared with placebo, no intervention, or other dietary interventions regardless of route of administration, dose or amount.

Data collection and analysis

Studies were assessed for inclusion and data extracted using a standardised data extraction form. We calculated risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, both with 95% confidence intervals (CI).

Main results

We included five studies (379 adult participants) that investigated a range of interventions. Lack of similarity among interventions investigated meant that data could not be pooled. Overall, study methodology was not adequately reported in any of the included studies. There was a high risk of bias associated with blinding (although it seems unlikely that outcomes measures were unduly influenced by lack of intervention blinding), random sequence generation and allocation methodologies were unclear in most studies, but selective reporting bias was assessed as low.

One study (120 participants) compared a low calcium diet with a normal calcium, low protein, low salt diet for five years. There was a significant decrease in numbers of new stone recurrences in those treated with the normal calcium, low protein, low salt diet (RR 0.77, 95% CI 0.61 to 0.98). This diet also led to a significant decrease in oxaluria (MD 78.00 µmol/d, 95% CI 26.48 to 129.52) and the calcium oxalate relative supersaturation index (MD 1.20 95% CI 0.21 to 2.19).

One study (210 participants) compared a low salt, normal calcium diet with a broad diet for three months. The low salt, normal calcium diet decreased urinary calcium (MD -45.00 mg/d, 95% CI -74.83 to -15.17) and oxalate excretion (MD -4.00 mg/d, 95% CI -6.44 to -1.56).

A small study (17 participants) compared the effect of dietary fibre as part of a low calcium, low oxalate diet over three weeks, and found that although calciuria levels decreased, oxaluria increased.

Phyllanthus niruri plant substrate intake was investigated in a small subgroup with hypercalciuria (20 participants); there was no significant effect on calciuria levels occurred after three months of treatment.

A small cross-over study (12 participants) evaluating the changes in urinary supersaturation indices among patients who consumed calcium-fortified orange juice or milk for one month found no benefits for participants.

None of the studies reported any significant adverse effects associated with the interventions.

Authors' conclusions

Long-term adherence (five years) to diets that feature normal levels of calcium, low protein and low salt may reduce numbers of stone recurrences, decrease oxaluria and calcium oxalate relative supersaturation indexes in people with idiopathic hypercalciuria who experience recurrent kidney stones. Adherence to a low salt, normal calcium level diet for some months can reduce calciuria and oxaluria. However, the other dietary interventions examined did not demonstrate evidence of significant beneficial effects.

No studies were found investigating the effect of dietary recommendations on other clinical complications or asymptomatic idiopathic hypercalciuria.

Résumé scientifique

Interventions diététiques pour la prévention des complications en cas d'hypercalciurie idiopathique

Contexte

L'hypercalciurie idiopathique est une anomalie métabolique congénitale qui se caractérise par des quantités excessives de calcium excrétées dans l'urine par des personnes dont les niveaux de calcium sérique sont normaux. La morbidité associée à l'hypercalciurie idiopathique est principalement liée à l'urolithiase et à la déminéralisation osseuse entraînant l'ostéopénie et l'ostéoporose. L'hypercalciurie idiopathique contribue à l'urolithiase à tous les stades de la vie ; les personnes atteintes de cette affection sont sujettes à la formation de calculs rénaux composés d'oxalate et de phosphate de calcium. Dans certains cas, des dépôts de calcium cristallisé se forment dans l'interstitium rénal, entraînant une augmentation du taux de calcium dans les reins. Chez l'enfant, l'hypercalciurie idiopathique peut entraîner un éventail de co-morbidités y compris l'hématurie récurrente macroscopique ou microscopique, le syndrome de dysurie-pollakiurie, les infections des voies urinaires et les douleurs abdominales et lombaires. Diverses interventions diététiques ont été décrites visant à réduire les niveaux de calcium urinaire ou la cristallisation urinaire.

Objectifs

Nos objectifs étaient d'évaluer l'efficacité, l'efficience et l'innocuité des interventions diététiques pour la prévention des complications de l'hypercalciurie idiopathique (urolithiase et ostéopénie) chez l'adulte et l'enfant, et d'évaluer les bénéfices des interventions diététiques dans la diminution de la symptomatologie urologique chez l'enfant atteint d'hypercalciurie idiopathique.

Stratégie de recherche documentaire

Nous avons contacté le coordinateur de recherche d'études du groupe Cochrane sur la néphrologie afin d'effectuer des recherches dans le registre spécialisé (le 23 avril 2013) en utilisant des termes de recherche pertinents pour cette revue. Les études répertoriées dans le registre spécialisé ont été identifiées par des stratégies de recherche spécifiquement conçues pour CENTRAL, MEDLINE et EMBASE.

Critères de sélection

Nous avons inclus tous les essais contrôlés randomisés (ECR) et quasi randomisés examinant les interventions diététiques visant à prévenir les complications de l'hypercalciurie idiopathique, par rapport à un placebo, à l'absence d'intervention ou à d'autres interventions diététiques indépendamment de la voie d'administration, de la dose ou de la quantité.

Recueil et analyse des données

Les études ont été évaluées pour inclusion et les données ont été extraites en utilisant un formulaire d'extraction de données standardisé. Nous avons calculé les risques relatifs (RR) pour les résultats dichotomiques et les différences moyennes (DM) pour les résultats continus, avec des intervalles de confiance (IC) à 95 %.

Résultats principaux

Nous avons inclus cinq études (379 participants adultes) qui examinaient un éventail d'interventions. En raison du manque de similarités entre les interventions examinées, les données n'ont pas pu être regroupées. Dans l'ensemble, la méthodologie n'était correctement rapportée dans aucune des études incluses. Il y avait un risque élevé de biais associé à la mise en aveugle (bien qu'il semble peu probable que les critères de jugement mesurés aient été indûment influencés par un manque de mise en aveugle dans les interventions), tandis que la génération de séquences aléatoires et la méthodologie d'assignation n'étaient pas clairement expliquées dans la plupart des études, même si le biais de reporting a été évalué comme étant faible.

Une étude (120 participants) comparait sur cinq ans une alimentation pauvre en calcium à un régime alimentaire avec des apports normaux en calcium pauvre en protéines et en sel. Il y avait une réduction significative du nombre de nouveaux calculs chez les personnes suivant le régime avec des apports normaux en calcium et pauvre en protéines et en sel (RR 0,77, IC à 95 % 0,61 à 0,98). Ce régime a également entraîné une diminution significative de l'hyperoxalurie (DM de 78,00 µmol/j, IC à 95 % 26,48 à 129,52) et de l'indice de supersaturation relative en oxalate de calcium (DM de 1,20, IC à 95 % 0,21 à 2,19).

Une étude (210 participants) comparait sur trois mois une alimentation pauvre en sel avec des apports normaux en calcium et un régime alimentaire varié. Le régime pauvre en sel aux apports calciques normaux a réduit le calcium urinaire (DM -45,00 mg/j, IC à 95 % -74,83 à -15,17) et l'excrétion d'oxalate (DM -4,00 mg/j, IC à 95 % -6,44 à -1,56).

Une petite étude (17 participants) comparait sur trois semaines l'effet de fibres alimentaires dans le cadre d'un régime pauvre en calcium et en oxalate et a observé que, bien que les niveaux de calciurie baissaient, l'hyperoxalurie augmentait.

Un apport de substrat végétal à base de Phyllanthus niruri a été étudié dans un petit sous-groupe atteint d'hypercalciurie (20 participants) ; aucun effet significatif sur les niveaux de calciurie n'a été observé après trois mois de traitement.

Une petite étude croisée (12 participants) évaluant les changements dans les indices de supersaturation urinaire chez des patients ayant consommé du jus d'orange ou du lait enrichi en calcium pendant un mois n'a révélé aucun effet bénéfique pour les participants.

Aucune des études ne rapportait d'effets indésirables significatifs associés aux interventions.

Conclusions des auteurs

L'observance à long terme (cinq ans) d'un régime alimentaire avec des niveaux de calcium normaux pauvre en protéines et en sel pourrait réduire les récidives de calculs et diminuer l'hyperoxalurie ainsi que les indices de supersaturation relative en oxalate de calcium chez les personnes atteintes d'hypercalciurie idiopathique souffrant de calculs rénaux récurrents. L'observance d'un régime pauvre en sel avec des apports calciques normaux pendant quelques mois peut réduire les niveaux de calciurie et d'hyperoxalurie. Cependant, les autres interventions diététiques examinées n'ont pas apporté de preuve d'effets bénéfiques significatifs.

Aucune étude n'a été trouvée concernant l'effet des recommandations alimentaires sur d'autres complications cliniques ou sur l'hypercalciurie idiopathique asymptomatique.

Plain language summary

Dietary interventions for preventing complications in idiopathic hypercalciuria

Hypercalciuria, an inherited metabolic condition, is the presence of excessive calcium in the urine. The cause is often unknown (idiopathic), and may occur in people who are otherwise well. Although people with the condition have normal levels of calcium in their blood, calcium is lost through the urine.

Adults with hypercalciuria are prone to developing kidney stones and losing calcium from their bones. In children, hypercalciuria can cause blood in the urine (haematuria), frequency-dysuria syndrome (frequent painful or difficult urination), urinary tract infections, abdominal and back pain.

It has been suggested that altering the diets of people with hypercalciuria could help to prevent complications of the condition. We therefore aimed to evaluate the benefits and harms of dietary interventions that had been investigated in clinical studies. We included five studies in our review, one of which compared a low calcium diet with a diet that included normal levels of calcium, low protein, low salt over five years. This study found that diets unrestricted for calcium intake significantly decreased numbers of new kidney stones.

Other dietary interventions, such as unprocessed wheat bran, did not show any evidence of beneficial effects.

We did not find any studies in children, and none investigating specific dietary recommendations for those who had hypercalciuria without symptoms.

Résumé simplifié

Les interventions diététiques pour la prévention des complications en cas d'hypercalciurie idiopathique

L'hypercalciurie, une affection métabolique héréditaire, est la présence d'un excès de calcium dans les urines. La cause en est souvent inconnue (idiopathique), et elle peut se produire chez des personnes qui se portent par ailleurs bien. Bien que le niveau de calcium dans le sang des personnes atteintes de cette affection soit normal, le calcium est éliminé dans l'urine.

Les adultes atteints d'hypercalciurie sont sujets à la formation de calculs rénaux et à la perte de calcium osseux. Chez les enfants, l'hypercalciurie peut occasionner la présence de sang dans les urines (hématurie), un syndrome de dysurie fréquente (miction fréquente douloureuse ou difficile), des infections des voies urinaires et des douleurs abdominales ou dorsales.

Il a été suggéré que la modification de l'alimentation des personnes atteintes d'hypercalciurie peut aider à prévenir les complications de la maladie. Nous avons donc cherché à évaluer les bénéfices et les inconvénients des interventions diététiques considérées dans des études cliniques. Nous avons inclus cinq études dans notre revue, dont l'un comparait sur cinq ans une alimentation pauvre en calcium à un régime alimentaire avec des apports normaux en calcium pauvre en protéines et en sel. Cette étude a constaté que les régimes sans restriction de l'apport en calcium réduisaient significativement le nombre de nouveaux calculs rénaux.

D'autres interventions diététiques, tels que le son de blé complet, n'ont apporté aucune preuve d'effets bénéfiques.

Nous n'avons pas trouvé d'études portant sur des enfants, ni aucune étude examinant des recommandations alimentaires spécifiques pour les personnes atteintes d'hypercalciurie sans symptômes.

Notes de traduction

Traduit par: French Cochrane Centre 15th June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Streszczenie prostym językiem

Interwencje dietetyczne w zapobieganiu powikłaniom idiopatycznej hiperkalciurii

Hiperkalciuria, dziedziczne zaburzenie metaboliczne, to zwiększone wydalanie wapnia z moczem. Jej przyczyna często jest nieznana (idiopatyczna) i może występować u osób, które czują się dobrze. Mimo, że osoby z tym zaburzeniem mają prawidłowe stężenie wapnia we krwi, to tracą wapń poprzez wydalanie z moczem.

Dorośli z hiperkalciurii są podatni na rozwój kamicy nerkowej oraz utratę wapnia z kości. U dzieci, hiperkalciuria może powodować występowanie krwi w moczu (krwiomocz), zespół częstego oddawania moczu (częste bolesne i utrudnione oddawanie moczu), zakażenia dróg moczowych oraz ból brzucha i pleców.

Sugeruje się, że zmiana diety u osób z hiperkalciurią może pomóc zapobiec powikłaniom związanym z tą chorobą. Dlatego też naszym celem była ocena korzyści i szkód wynikających ze stosowania interwencji dietetycznych, które oceniano w badaniach klinicznych. Do naszego przeglądu włączyliśmy 5 badań. W jednym badaniu porównywano stosowanie diety o małej zawartości wapnia i diety o standardowej zawartości wapnia, ale o małej zawartości białka i soli, w okresie 5 lat. Stwierdzono, że mało restrykcyjna dieta, w której nie ograniczano przyjmowania wapnia, wiązała się z istotnym zmniejszeniem liczby nowych kamieni nerkowych.

Nie wykazano, aby stosowanie innych interwencji żywieniowych, takich jak spożywanie nieprzetworzonych otrębów pszennych, przyniosło jakiekolwiek korzystne efekty.

Nie odnaleźliśmy żadnych badań, które obejmowały populację dzieci oraz żadnych badań, w których oceniano stosowanie szczegółowych zaleceń żywieniowych u osób z bezobjawową hiperkalciurią.

Uwagi do tłumaczenia

Tłumaczenie: Magdalena Koperny, Redakcja: Karolina Moćko

Background

Idiopathic hypercalciuria is a relatively common hereditary metabolic anomaly. Reported prevalence rates in the healthy population vary between 2.9% and 6.5% (Caballero 2000).

Idiopathic hypercalciuria is defined as daily urinary calcium excretion of > 250 mg for women, and 275 to 300 mg for men, whose diet is unrestricted, and in the absence of secondary causes such as primary hyperparathyroidism, renal tubular acidosis, malignancy, vitamin D intoxication, immobilisation, hyperthyroidism, or Bartter's syndrome (Langman 1984). The condition has also been defined as excretion of urinary calcium > 4 mg/kg body weight/d in children (Ghazali 1974).

Although hypercalciuria is thought to be related to osteopenia and osteoporosis, the pathophysiological mechanisms of bone loss are unknown. Dietary issues, genetic factors, hormonal influences, and local cytokines appear to be associated with altered bone formation in people with hypercalciuria (Asplin 2003; Freundlich 2002; Sakhaee 2011). People with hypercalciuria have negative calcium balance - the amount of calcium excreted in urine exceeds the amount consumed; and therefore, all instances of hypercalciuria have bone involvement (Pak 2003). It has been estimated that 30% to 40% of children and adults with idiopathic hypercalciuria have osteopenia. Osteopenia increases osteoporotic fracture risk in adults, but the long-term impact remains unknown in children (Garcia-Nieto 1997; Sakhaee 2011).

Description of the condition

Idiopathic hypercalciuria is complex condition attributed to factors that affect calcium-phosphorus metabolism. Hypercalciuria contributes to kidney stone disease in both adults and children (Stapleton 1987). In industrialised nations, kidney stones occur in 15% of men and 6% of women, and recurrence is approximately 50% (Bihl 2001).

Hypercalciuria in people whose calcium levels are normal may be classified as absorptive (types I and II), renal hypercalciuria, and renal phosphate leak (absorptive hypercalciuria type III) types. However, subtypes are not well defined clinically, and patients may have features common to more than one type. Mechanisms include reduced kidney tubule reabsorption and calcium transport. Parathyroid hormone (PTH) is widely accepted to play a significant role in altering urinary calcium levels, but this is unlikely sufficient account for the total effect found among people with hypercalciuria (Worcester 2007). Loss of renal phosphate in the presence of normal PTH plasma levels increases calciuria, independent of calcium intake. Hypophosphataemia caused by renal phosphate leakage may contribute to calcium stone formation by increasing serum calcitriol, calcium excretion, and urinary saturation (Prie 2001; Williams 1996).

Calcium stones attach to areas of renal papillae that contain interstitial apatite deposits. Deposits of calcium phosphate that originate in the ascending limb of the loop of Henle, known as Randall's plaques, form in response to high levels of calcium in the urine, reduced urine volume, and pH causing loss of urothelial integrity (Kuo 2003). Urinary proteins with affinity for apatite form layers covering exposed plaques. When urine supersaturation exceeds the moderating effects of these proteins, aggregated crystals create stones (Evan 2007). Stone formation is inhibited by magnesium, citrate, and pyrophosphate which prevent crystallisation. About 80% of all kidney stones contain calcium, and at least 40% to 60% of all people who develop calcium stones are found to have hypercalciuria (Lerolle 2002).

In children, hypercalciuria can cause a wide range of symptoms: the most common is recurrent macroscopic or microscopic haematuria. Other common manifestations in children are frequency-dysuria syndrome, abdominal and lumbar pain. Recurrent urinary infection is also common (Vachvanichsanong 2001).

Urinary tract stone-related morbidity is primarily related to obstruction and pain, although non-obstructing stones can be responsible for considerable discomfort. Obstructing stones can be asymptomatic, which is a factor in the outcomes of the relatively small number of people who experience kidney loss from chronic, untreated obstruction. Although kidney stones are not a significant cause of kidney failure, epidemiological data suggest that most people who develop kidney stones have mildly compromised kidney function (Gillen 2005). The most potentially dangerous aspect of stone disease is the combination of obstruction and infection of the upper urinary tract, which can result in pyelonephritis, pyonephrosis (gross pus in the renal collecting system) and urosepsis (Leslie 2000).

Description of the intervention

Dietary interventions - often involving increased fluid intake - may be suggested for people with idiopathic hypercalciuria, particularly for those who have histories of stone disease with the aim of decreasing urinary calcium supersaturation (Rodgers 2002). Although an observational study reported benefits from increasing fluid intake (Curhan 1998), a later study indicated that although increased fluids reduced urinary stone recurrence, it was not beneficial for primary prevention (Qiang 2004).

There is lack of consensus about reducing dietary calcium intake: there are indications that this may prevent oxalate absorption in the digestive tract. Although benefits have been reported relating to moderate calcium intake (600 to 800 mg/d) to reduce oxaluria and minimise osteopenia risk, evidence also suggests that excessive dietary calcium (> 2000 mg/d) could counteract any protective effects on oxalate absorption and promote hypercalcaemia, hypercalciuria and stone formation (Bataille 1983; Coe 1982; Curhan 1997b; Fuss 1990; Harward 1993; Lemann 1996).

Diets high in animal protein may impose negative effects on people with hypercalciuria by inducing acid overload, inhibiting renal reabsorption of calcium, and increasing urinary excretion. Excess acid may be neutralised, at least partly, by releasing skeletal calcium phosphate into the bloodstream, contributing to increased hypercalciuria. Further problems arise from metabolising animal proteins to purines. Purines are precursors of uric acid, which when plasma levels rise, facilitate formation of uric acid stones. Purines also contribute to excretion of urinary calcium (Moe 2006).

High protein intake has been associated with increased risk of stone formation (Curhan 1993); other studies comparing increased water intake and reduced protein diet have found a very small protective effect (Breslau 1988; Curhan 1993; Curhan 1997a; Hiatt 1996; Liatsikos 1999). Siener 2005 identified low fluid intake and increased protein and alcohol intake as significant dietary risk factors.

It has been suggested that restricting dietary oxalate could be a protective factor (Assimos 2000). People with high intakes of ascorbic acid excreted high levels of oxalate, but were not found to be more likely to develop stones (Curhan 1999).

High levels of dietary sodium intake have also been linked to risk of developing hypercalciuria and stones. Bone calcium release increases when salt intake is high, and the direct effect of sodium on the kidney is increased calcium excretion (Bourdeau 1994 ; Frassetto 2007 ). Salt restriction has been correlated with decreased calciuria levels in people with hypercalciuria (Breslau 1982; Martini 2000; Muldowney 1982; Sakhaee 1993). Evidence suggest that diets to reduce calcium and oxalate excretion by restricting intake of dietary calcium, oxalate, sodium, and meat products were beneficial in reducing urinary calcium oxalate saturation in people with hypercalciuria (Pak 2005).

A relatively low intake of potassium may promote stone formation in susceptible people (Curhan 1993; Heilberg 2000).

Consumption of alcohol and coffee can affect onset of pathologies secondary to hypercalciuria. Ethanol from alcoholic drinks may decrease osteoblastic activity and PTH levels, increasing urinary excretion of calcium, leading to osteoporosis (de Vernejoul 1983; Garcia-Sanchez 1995). Excessive coffee drinking has been reported to increase calcium excretion (Morgan 1994). Among people who are susceptible to stone formation, restricting intake of soft drinks containing phosphoric acid could decrease incidence of stone formation (Shuster 1992).

Some plant infusions are thought to decrease stone recurrence in people who are not hypercalciuric (Premgamone 2001). Similarly, some fruit juices - such as cranberry juice - may be protective (McHarg 2003). However, for reasons that have not been fully explained, grapefruit juice was associated with increased risk of stone formation in two cohort studies conducted in a population who were not hypercalciuric (Curhan 1996; Curhan 1998).

Other dietary interventions include limiting refined carbohydrates, which may favour intestinal calcium absorption, and fibre consumption, which bonds to the free calcium in the intestinal lumen and may decrease its absorption (Ebisuno 1986; Jahnen 1992).

Phyllanthus niruri, a plant traditionally used in Brazil to treat urinary stones, was investigated (Nishiura 2004). Analysis of a subset of patients exhibiting hypercalciuria found that P. niruri reduced urinary calcium, but did not reduce stone voiding or provide pain relief.

Most studies analysing the effectiveness of dietary interventions for prevention of kidney stones address that the disease course is slow and variable. The average rate of stone formation in people who develop recurrent stones is approximately 0.15 to 0.20 stones/y (Tiselius 2000). Thus, studies that attempt to demonstrate the efficacy of specific treatment programs must last for several years.

Why it is important to do this review

We analysed the various dietary strategies for controlling the disease clinically to see if it was possible to control the disease metabolically and to decrease the levels of excretion of urinary calcium, and to reduce the main clinical manifestations.

For the dietary management of hypercalciuria it is necessary to consider two basic factors which are particularly important in the formation of kidney stones and bone health.

  • It should be established dietary strategies aimed to reduce calcium or oxalate excretion, intended to achieve lower calcium oxalate complex formation. These diets may promote the prolonged reduction of one or both metabolites mentioned to reduce the incidence of new kidney stones

  • Simultaneously it is necessary to design dietary strategies that do not generate a negative calcium balance that may cause bone-loss.

To achieve these two objectives is logical to think that the structure of the diet should be balanced, and will affect more than one component. Therefore the most effective diet is likely to be a multicomponent diet.

Objectives

Our objectives were to assess:

  • the efficacy, effectiveness and safety of dietary interventions for preventing complications in idiopathic hypercalciuria (urolithiasis and osteopenia) in adults and children; and

  • the benefits of dietary interventions in decreasing urological symptomatology in children with idiopathic hypercalciuria.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the benefits and harms of dietary interventions for preventing complications in people with idiopathic hypercalciuria.

Types of participants

Inclusion criteria

We included people (men and women, adults and children) with hypercalciuria, regardless of stone formation status, among whom dietary interventions were introduced with the aim of decreasing risk or recurrence of stones, and to eliminate symptoms such as dysuria, haematuria, and abdominal pain. Hypercalciuria was defined as daily urinary excretion of more than 300 mg Ca/d (7.5 mmol) in adult men and > 250 mg Ca/d (6.25 mmol) in adult women who were on regular unrestricted diets; or excretion of urinary calcium of > 4 mg/kg body weight/d in children and adults.

Exclusion criteria

We excluded participants with secondary hypercalciuria, such as primary hyperparathyroidism, renal tubular acidosis, malignancy, vitamin D intoxication, immobilisation, hyperthyroidism, Bartter's syndrome, sarcoidosis, sponge kidney, or conditions associated with causing osteopenia or urolithiasis, such as primary hyperoxaluria, enteric hyperoxaluria, bowel resection, or inflammatory bowel disease. We further excluded those who were chronic users of drugs with capacity to increase risks of calcium stone formation, such as vitamin D, acetazolamide, and antiepileptic drugs.

Types of interventions

Studies investigating any dietary intervention aimed to prevent complications in people with idiopathic hypercalciuria compared with placebo, no interventions, other dietary intervention or a different administration mode or amount of the same treatment were eligible for inclusion. We assessed only studies with minimum durations of one year to evaluate effects on kidney stone recurrence and other urological symptoms, and a minimum of two weeks to assess effects of calcium or oxalate urinary excretion rates.

Types of outcome measures

Primary outcomes
  • Reduction in stone formation: stone rate or calcium stone recurrence, or increases in numbers of stone-free patients. Stone rate was defined as the number of stones per patient per year over a minimum duration of one year. New stone occurrence was defined by radiography, ultrasonography, pyelography or helical CT scan. All patients were stone-free before therapy

  • Reduction in episodes of renal colic

  • Increase or no reduction in bone mass: dual-energy X-ray, absorptiometry over a minimum duration of one year

  • Reduction in urinary symptoms: incidence of urinary tract infection (UTI), haematuria, dysuria, or enuresis in children over a minimum duration of six months

  • Improvement in quality of life in terms of days in hospital, days off work or school.

Secondary outcomes
  • Reduction in calciuria: decrease in 24 hour calciuria or urinary calcium/creatinine ratio

  • Reduction in oxaluria: decrease in 24 hour oxaluria or calcium oxalate relative supersaturation index

  • Reduction in creatinine clearance

  • Adverse events such as:

    • gastrointestinal side effects

    • changes in blood pressure

    • fluid/electrolyte imbalances: hyponatraemia, hypercalcaemia, hyperuricaemia, hypokalaemia, hypermagnesaemia, hyperchloraemia, acidosis, hyperglycaemia, hypocitraturia.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Renal Group's Specialised Register (23 April 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from:

  • Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  • Weekly searches of MEDLINE OVID SP

  • Handsearching of renal-related journals and the proceedings of major renal conferences

  • Searching the current year of EMBASE OVID SP

  • Weekly current awareness alerts for selected renal journals

  • Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of nephrology textbooks, review articles and relevant studies.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies relevant to the review. Titles and abstracts were screened independently by all authors. All authors independently assess retrieved abstracts, and if necessary the full text of these studies, to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data were extracted independently by at least three authors using standard data extraction forms. Studies reported in languages other than English or Spanish were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was included. Where relevant outcomes were only published in earlier versions, these data were used. Any discrepancies between published versions were to be highlighted. Any further information required from the original author was requested by written correspondence, and any relevant information obtained in this manner was included in the review. Disagreements were resolved in consultation with another member of the author team.

Assessment of risk of bias in included studies

The following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (new stones, osteopenia, haematuria, frequency-dysuria syndrome, UTI, gastrointestinal side effects) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (decrease in 24 hour calciuria or urinary calcium/creatinine ratio, blood pressure, serum creatinine, natraemia, calcaemia, uricaemia, kalaemia, magnesaemia, chloraemia, acidosis, glycaemia, oxaluria and citraturia), the mean difference (MD) was used, or the standardised mean difference (SMD) where different scales were used.

Dealing with missing data

Missing data relevant to this review were sought from authors where necessary. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population was carefully performed. Attrition rates, such as drop-outs, losses to follow-up and withdrawals were investigated. Issues of missing data and imputation methods (e.g. last-observation-carried-forward) were critically appraised (Higgins 2011).

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

We had planned that if sufficient RCTs were identified, examination for reporting bias was to be undertaken using a funnel plot (Higgins 2011). This could not be undertaken because there were insufficient studies identified to enable meaningful funnel plot construction.

Data synthesis

Data were pooled using the random-effects model, but the fixed effect model was also analysed to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was to be undertaken to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to stone disease history or age. Heterogeneity in the interventions could be related to dietary intervention duration, or participant compliance to dietary measures. Adverse effects were to be tabulated and assessed using descriptive techniques because they were likely to differ among the interventions investigated. Where possible, risk difference with 95% CI was to be calculated for each adverse effect, either compared with no treatment or another agent.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

The search strategy described identified 317 references. Titles and abstracts were screened and 171 studies were selected. After further screening 27 records were selected for full text review. After exclusions, five RCTs were included in our analysis. Figure 1 depicts the results of our search strategy.

Figure 1.

Study flow diagram

Included studies

We included five studies that involved a total of 379 adult participants (Borghi 2002; Gleeson 1990; Nishiura 2004; Coe 1992; Nouvenne 2010). With the exception of the cross-over study by Coe 1992, all other studies were parallel RCTs that reported on participants with idiopathic hypercalciuria. None of the included studies included children. All outcomes were assessed at the end of the intervention. Studies were classified according to the dietary interventions investigated, but because different interventions were investigated, results could not be pooled for meta-analysis. All studies were published in English.

  • Borghi 2002 (120 male participants) compared the effects of two diets over five years. One diet aimed to reduce calcium intake (10 mmol/d), and the other reduced protein (< 15% of total energy) and salt (< 50 mmol/d) and included normal-to-high calcium intake (approximately 30 mmol/d). Fluid intake of 2 to 3 L/d of non-mineral water was also recommended for both groups.

  • Nouvenne 2010 (210 participants) compared the effect of two diets over three months. Low salt diet (salt < 60 mmol/d) participants (108) were asked to eliminate kitchen salt, strictly limit consumption of high salt content foods and maintain normal calcium intake (800 to 1000 mg/d) by including milk and dairy products. Participants (102) in the control group were asked to maintain their normal dietary habits, and no specific recommendations about calcium or salt intake were provided. Fluid intake of 2 to 3 L/d of a specific mineral water with low sodium and calcium content (Fiuggi water) was also recommended for both groups.

  • Gleeson 1990 (17 participants) analysed the hypocalciuric effects of unprocessed wheat bran (78 g/d) for three months. Both groups followed diets that limited calcium (300 to 350 mg/d) and oxalate intake. One group added wheat bran to their diet. All participants were administered hydrochlorothiazide (50 mg/12 h) and potassium citrate (5 mEq/8 h) over the following week.

  • Nishiura 2004 (20/69 idiopathic hypercalciuria participants) prospectively evaluated P. niruri plant substrate intake on 24 hour urinary biochemical parameters to assess in vivo effects. The study's 20 participants with idiopathic hypercalciuria were randomised to receive either P. niruri (8) (450 mg capsules three times/d) or placebo (12) for three months. Dietetic and pharmacological co-interventions were not specified in the report.

  • Coe 1992 (12 participants) evaluated changes in urinary supersaturation in healthy, non-stone-forming participants with who consumed calcium-fortified orange juice or milk in a cross-over study over four weeks. Participants followed a free diet that included a calcium supplement (600 mg/d) administered as skim milk or orange juice fortified with calcium-citrate-malate salt.

Excluded studies

We excluded 18 studies (22 records) after full-text assessment: four were not RCTs (Colette 1993; Jaeger 1982; Muller 2001; Schwille 1997); seven investigated populations that were not relevant to this review (Aras 2008; Baxmann 2003; Bellizzi 1999; Domrongkitchaiporn 2004; Lamid 1984; Matsumoto 2006; van Faassen 1998); one investigated an intervention not relevant to this review (Ala-Opas 1987); and relevant subgroup data analyses were not available in six papers (Borghi 1996; Campoy Martinez 1994; Hiatt 1996; Karagulle 2007; Kocvara 1999; Rotily 2000).

Risk of bias in included studies

Overall, study methodology was not adequately reported in any of the included studies (Figure 2; Figure 3). There was a high risk of bias associated with blinding (although it seems unlikely that outcomes measures were unduly influenced by lack of intervention blinding), random sequence generation and allocation methodologies were unclear in most studies, but selective reporting bias was assessed as low.

Figure 2.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies

Figure 3.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study

Allocation

Borghi 2002 and Nouvenne 2010 adequately described sequence generation of participant randomisation and allocation; Coe 1992, Gleeson 1990 and Nishiura 2004 did not specify randomisation methods applied.

Blinding

Only Nishiura 2004 adequately described blinding of participants. The nature of the interventions meant that participants were not blinded in Borghi 2002, Coe 1992, Gleeson 1990 or Nouvenne 2010; however, it is unlikely that outcome measures were influenced by lack of blinding.

Incomplete outcome data

Follow-up was complete, or near complete in Borghi 2002 and Nouvenne 2010. Borghi 2002 reported that 17 participants (14%) withdrew from the study. Nouvenne 2010 reported that 13 participants withdrew: two in Group A (due to work problems to assist visits) and 11 in Group B (due to adaptation problems to low salt diet). Coe 1992, Gleeson 1990 and Nishiura 2004 did not report attrition rates.

Other potential sources of bias

A pharmacological co-intervention was included at the end of one study (Gleeson 1990). In Nishiura 2004 possible differences in co-interventions between groups were not excluded. Nouvenne 2010 was conducted in participants having a special baseline characteristic (high salt content diet intake).

No other potential threats to validity were detected.

Effects of interventions

Low calcium diet versus normal calcium, low protein, low salt diet

Only Borghi 2002 could be analysed for this intervention. Gleeson 1990 investigated reduced calcium and oxalate intake; however, both groups followed similar calcium restricted diets, so comparison could not be made. Nouvenne 2010 investigated reduced salt and normal calcium diets, but analyses of protein intake were not provided and because calcium intake was not controlled; outcomes were therefore not comparable.

Kidney stones

We assessed the total number of patients reported by Borghi 2002 who had no new recurrences during follow-up. This study found a significant decrease among those assigned to the normal calcium, low protein, low salt diet (Analysis 1.1 (1 study, 120 participants): RR 0.77, 95% CI 0.61 to 0.98). We were unable to determine the numbers of kidney stone recurrences to establish the stone formation rate because participants were excluded as they experienced stone events.

Urinary metabolite levels

At one week Borghi 2002 reported a decrease in calciuria in the normal calcium, low protein, low salt diet participants (6.1 ± 2.2 versus 8.3 ± 3.4). However, the effect was not sustained; there was no significant decrease in calciuria at five years (Analysis 1.2 (1 study, 68 participants): MD 0.30 mmol/d, 95% CI -0.57 to 0.1.17).

In contrast, effects of the normal calcium, low protein low salt diet on oxalate daily urinary excretion was sustained. Oxaluria decreased significantly in this group compared with low calcium diet group at five years (Analysis 1.3 (1 study, 68 participants): MD 78.00 µmol/d, 95% CI 26.48 to 129.52). Calcium oxalate relative supersaturation index decreased significantly throughout the study, reflecting a decrease in the risk of urinary crystallisation, and possibly an indirect decrease in the risk of urinary stones in the low calcium diet group (Analysis 1.4 (1 study, 68 participants): MD 1.20, 95% CI 0.21 to 2.19).

Other results

No metabolic or gastrointestinal side effects were described. Seven low calcium intake participants withdrew because of hypertension - a possible adverse effect of low calcium intake. We therefore analysed blood pressure changes in both groups during follow-up; no significant differences were determined (Analysis 1.5 (1 study, 120 participants): RR 7.00, 95% CI 0.89 to 55.17).

Low salt, normal calcium diet versus a normal salt diet

Nouvenne 2010 investigated the effects of a low salt, normal calcium diet on 210 people with histories of calcium stone formation for three months. This study reported low salt diet group participants had lower urinary sodium (68 ± 43 mmol/d at three months versus 228 ± 57 mmol/d at baseline, P < 0.001). This group also showed a significantly lower level of urinary calcium compared with normal salt diet group (Analysis 2.1 (1 study, 210 participants): MD -45.00 mg/d, 95% CI -74.83 to -15.17) as well as a significantly lower oxalate excretion (Analysis 2.2 (1 study, 210 participants): MD - 4.00 mg/d, 95% CI -6.44 to -1.56) at three months. When expressed in relation to a sodium diet reduction of 100 mmol, calcium excretion decreased by approximately 64 mg/100 mmol sodium. Urinary calcium was within the normal range in 61.9% of low salt, normal calcium diet participants and 34.0% on the control diet (difference + 27.9%, 95% CI 14.4% to 41.3%, P < 0.001).

Phyllanthus niruri versus placebo

Nishiura 2004 assessed P. niruri, a plant used in Brazil to treat urinary calculi, to investigate its effect in reducing lithogenic metabolic urinary abnormalities. P. niruri was compared to placebo over three months in a subgroup of 20 participants with idiopathic hypercalciuria. Although people treated with the plant extract had significantly reduced calciuria compared with baseline values, there was no significant difference between groups at the end of follow-up (Analysis 3.1 (1 study, 20 participants): MD -1.10 mg/kg/d, 95% CI -2.37 to 0.17). Serum biochemical parameters were not significantly different following P. niruri or placebo administration.

Unprocessed wheat bran

Gleeson 1990 analysed the hypocalciuric effect of dietary fibre added to a low calcium, low oxalate diet for a period of three weeks in 17 people with idiopathic hypercalciuria. Calciuria decreased significantly in the unprocessed wheat bran group (Analysis 4.1 (1 study, 17 participants): MD -64.80 mg/d, 95% CI -98.94 to -30.66). The daily additional dietary fibre contained 164 mg of oxalate, so the treatment group received an oxalate-enriched diet. As expected, oxalate increased significantly in the unprocessed wheat bran group (Analysis 4.2 (1 study, 17 participants): MD 13.70 mg/d, 95% CI 8.37 to 19.03). The overall effect on the risk of urinary crystallisation was therefore uncertain.

Calcium-fortified orange juice and milk

Coe 1992 evaluated milk and orange juice fortified with calcium citrate malate for potential to alter urine chemistries and crystallisation during an 11 week cross-over study (12 participants). Results were analysed by gender (M/F: 6/6). Daily urinary calcium excretion was not significantly affected by either supplement in either gender. Supplementary calcium (600 mg) did not increase calciuria from baseline (241 ± 30 mg/d versus 234 ± 16 mg/d in men, and 180 ± 20 mg/d versus 216 ± 11 mg/d in women for the milk supplement; and 241 ± 30 mg/d versus 242 ± 16 mg/d in men and 180 ± 20 mg/d versus 214 ± 15 mg/d in women for orange juice supplement).

Fortified orange juice significantly increased urinary pH relative to milk in both men and women (6.22 ± 0.09 versus 8.96 ± 0.08 in men and 6.54 ± 0.08 versus 6.24 ± 0.10 in women) and urinary citrate concentration in women only (540 ± 57 mg/L versus 358 ± 31 mg/L); no difference in daily citrate excretion was observed. Both urinary parameters were significantly increased by orange juice in both men and women relative to baseline (544 ± 46 mg/d versus 517 ± 49 mg/d in men and 689 ± 30 mg/d versus 515 ± 47 mg/d in women).

Urinary relative supersaturation indices for calcium oxalate, brushite and calcium carbonate did not vary significantly between dietary supplements. The calcium carbonate supersaturating index increased significantly in groups who received supplements relative to baseline values.

Due to the small number of studies identified we were unable to perform subgroup analyses to investigate heterogeneity, perform sensitivity analyses, assess publication biases, or tabulate adverse events as stated in our protocol.

Discussion

This review identified five studies (379 participants) that assessed the effects of different dietary interventions to prevent complications in people with idiopathic hypercalciuria. Overall, the included studies were assessed as moderate methodological quality and risk of bias.

We were unable to conduct meta-analysis because of lack of similarity among interventions which did not permit the data to be pooled. Furthermore, we found no studies that investigated dietary interventions among children with hypercalciuria, or that analysed the effect of an isolated reduction of dietary calcium on stone recurrence in people with hypercalciuria.

Although, none of the studies reported any significant adverse effects associated with the dietary interventions investigated, no compelling evidence was identified to support the use of dietary interventions to reduce the risk of complications among people with idiopathic hypercalciuria.

Summary of main results

Borghi 2002 compared low calcium diet with normal calcium, low protein, low salt diet for five years. There was a significant decrease in numbers of new stone recurrences in those who followed normal calcium, low protein, low salt diets (RR 0.77, 95% CI 0.61 to 0.98). People on this diet also had significant decreases in oxaluria and in the calcium oxalate relative supersaturation index.

Borghi 2002 compared a broad diet that included normal intake of calcium but low levels of sodium and protein, with a calcium-restricted diet for people with hypercalciuria who had histories of kidney stones. Urinary calcium was reduced in participants who adopted the broad diet in the short term, but this effect was not maintained over time. However, participants on the broad diet achieved consistent and permanent decreased oxaluria (MD 78 µmol/d), which improved calcium oxalate relative supersaturation index in urine for prolonged periods of time.

Isolated reduction of dietary calcium was less efficient than reducing sodium and protein combined with higher calcium intake. Although this diet was effective in controlling urinary metabolites in people with hypercalciuria, it could not be determined which aspects of the broad diet were most significant.

Nouvenne 2010 compared a low salt, normal calcium diet with an unrestricted diet over three months. The unrestricted diet decreased urinary calcium (MD -45.00 mg/d, 95% CI -74.83 to -15.17) and oxalate excretion (MD -4.00 mg/d, 95% CI -6.44 to -1.56).

Gleeson 1990 investigated inclusion of unprocessed wheat bran to a low calcium, low oxalate diet for three weeks. Dietary fibre was found to reduce calciuria (MD -64.80 mg/d), possibly by affecting calcium absorption. Reduction from baseline was 23%. However, unprocessed wheat bran is rich in oxalate, and caused increased oxaluria despite the base diet being low in oxalates. The overall effect on risk of stone development is controversial: the control group received a low calcium, low oxalate diet, with little positive effect on calciuria reduction.

Nishiura 2004 investigated the effect of P. niruri plant extract on 24 hour urinary biochemical parameters in a small subgroup with hypercalciuria. No significant effect on calciuria levels occurred after three months of treatment.

Coe 1992 evaluated dietary intake of 600 mg of calcium/d as skim milk or orange juice fortified with a mixed calcium citrate malate salt over four consecutive weeks. Compared with milk, fortified orange juice had no effect on urine chemistries in hypercalciuric adults, except that urine pH and citrate excretion increased. Theoretically, these changes prevent increases in the calcium oxalate supersaturation index, but study data did not demonstrate differences in calcium oxalate, brushite or calcium carbonate supersaturation indices. Thus, both beverage supplements had similar efficacies. Furthermore, neither supplement changed urinary calcium nor oxalate excretion levels with respect to baseline. These data indicate that either milk or calcium-fortified orange juice can be consumed as a dietary source of calcium without increasing the risk of stone formation in a hypercalciuric population. Because the study design did not enable clear comparison between non-restricted and calcium-supplemented diets or sources of calcium supplementation, these data should be interpreted cautiously. The study found no benefits for participants.

Overall completeness and applicability of evidence

We assessed five RCTs that investigated dietary interventions for preventing complications among people with idiopathic hypercalciuria. We were unable to obtain data relating to all pre-defined outcome measures because they were not all reported in the included studies.

Reporting in the included studies was suboptimal. Only two studies adequately reported adverse events and drop-outs.

Quality of the evidence

Overall, the quality of the evidence supporting dietary interventions is poor, since study methodology was not adequately reported in the included studies and only one study had low risk on most sources of bias.

Authors' conclusions

Implications for practice

We found limited and methodologically flawed evidence that compared with other diet-based strategies, prolonged normal calcium, low protein, low sodium diets may reduce numbers of stone recurrences in people with idiopathic hypercalciuria.

Limited quality evidence was also identified indicating that normal calcium, low protein, low sodium diets may decrease oxaluria and the calcium oxalate relative supersaturation index in people with symptomatic idiopathic hypercalciuria, without significant adverse effects.

Limited suboptimal evidence also indicated that compared with other dietary interventions, low sodium, normal calcium diet may reduce calciuria and oxaluria in people with idiopathic hypercalciuria and recurrent stones for some months.

Limited and flawed evidence suggested that including unprocessed wheat bran in the diet for short periods may reduce calciuria but increases oxaluria in people with idiopathic hypercalciuria.

We found no evidence to support that dietary interventions were beneficial in preventing formation of stones in people with asymptomatic idiopathic hypercalciuria.

Implications for research

Although there is limited evidence to suggest that normal calcium, low protein, low sodium diets over long periods may reduce numbers of stone recurrences and decrease urinary calcium oxalate supersaturation indices in men who are hypercalciuric, further well-designed, adequately powered studies are needed to evaluate effects on bone health. Future investigators should also consider designing parallel studies to assess other broad and inclusive dietary interventions with normal calcium, low protein, low sodium diets.

Larger studies over longer periods are required to investigate if low sodium and normal calcium diets can improve urinary calcium oxalate supersaturation indices in people with hypercalciuria to reduce numbers of stone recurrences and establish impact on bone health.

Well-designed, adequately powered, studies in children with idiopathic hypercalciuria are needed to determine if normal calcium, low sodium, low protein and high fluid diets can reduce urologic symptoms, kidney stone recurrence and improve bone health.

Well-designed RCTs are required to evaluate whether diet can reduce development of kidney stones and maintain bone health in adults and children with asymptomatic hypercalciuria.

Acknowledgements

We would like to thank the referees for their feedback and advice during the preparation of this review.

Data and analyses

Download statistical data

Comparison 1. Low calcium diet versus normal calcium, low protein, low salt diet
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 No new recurrences of kidney stones1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2 Urinary calcium levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
3 Urinary oxalate levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
4 Calcium oxalate relative supersaturation index1 Mean Difference (IV, Random, 95% CI)Totals not selected
5 Changes in blood pressure1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Low calcium diet versus normal calcium, low protein, low salt diet, Outcome 1 No new recurrences of kidney stones.

Analysis 1.2.

Comparison 1 Low calcium diet versus normal calcium, low protein, low salt diet, Outcome 2 Urinary calcium levels.

Analysis 1.3.

Comparison 1 Low calcium diet versus normal calcium, low protein, low salt diet, Outcome 3 Urinary oxalate levels.

Analysis 1.4.

Comparison 1 Low calcium diet versus normal calcium, low protein, low salt diet, Outcome 4 Calcium oxalate relative supersaturation index.

Analysis 1.5.

Comparison 1 Low calcium diet versus normal calcium, low protein, low salt diet, Outcome 5 Changes in blood pressure.

Comparison 2. Low salt, normal calcium diet versus normal salt diet
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Urinary calcium levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Urinary oxalate levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Low salt, normal calcium diet versus normal salt diet, Outcome 1 Urinary calcium levels.

Analysis 2.2.

Comparison 2 Low salt, normal calcium diet versus normal salt diet, Outcome 2 Urinary oxalate levels.

Comparison 3. Phyllanthus niruri versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Urinary calcium levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Phyllanthus niruri versus placebo, Outcome 1 Urinary calcium levels.

Comparison 4. Unprocessed wheat bran
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Urinary calcium levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Urinary oxalate levels1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 4.1.

Comparison 4 Unprocessed wheat bran, Outcome 1 Urinary calcium levels.

Analysis 4.2.

Comparison 4 Unprocessed wheat bran, Outcome 2 Urinary oxalate levels.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Hypercalciuria, this term only

  2. MeSH descriptor Calcium Metabolism Disorders, this term only

  3. (hypercalciuri*):ti,ab,kw in Clinical Trials

  4. (#1 OR #2 OR #3)

MEDLINE
  1. Hypercalciuria/

  2. hypercalciuri$.tw.

  3. Calcium Metabolism Disorders/

  4. or/1-3

EMBASE
  1. Idiopathic Hypercalciuria/

  2. hypercalciuria$.tw.

  3. or/1-2

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

Writing protocol and review: JE, AF, AB, NF, MR
Screening titles and abstracts: JE, AF, AB, NF, MR
Assessment for inclusion: JE, AF, AB, NF, MR
Quality assessment: JE, AF, AB, NF, MR
Data extraction: JE, AF, AB, NF
Data entry into RevMan: JE
Data analysis: JE, AB, MR
Disagreement resolution: MR

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Pediatrics. Hospital Universitari Sant Joan de Reus, Spain.

  • Universitat Rovira i Virgili, Spain.

  • Unitat de Recerca en Pediatria, Nutrició i Desenvolupament Humà. IISPV, Spain.

  • Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau, Spain.

  • Department of Pediatrics. Hospital General de Catalunya, Universitat Internacional de Catalunya, Spain.

External sources

  • Instituto de Salud Carlos III. Subdirección General de Investigación Sanitaria, (01/A060), Spain.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Borghi 2002

Methods
  • Study design: parallel RCT

  • Time frame: June 1993 to December 1994

  • Study duration: 5 years

Participants
  • Setting: single centre

  • Country: Italy

  • Men with idiopathic hypercalciuria (urinary calcium excretion, > 300 mg/d (7.5 mmol/d) on an unrestricted diet, recurrent formation of calcium oxalate stones (at least two documented events (colic episodes with expulsion of stones or radiographic evidence of retained stones)), no previous visit to a stone disease centre, no current treatment for the prevention of recurrent stones except for the advice to increase water intake

  • Number: treatment group 1 (60); treatment group 2 (60)

  • Mean age ± SD (years): treatment group 1 (45.4 ± 10.9); treatment group 2 (44.8 ± 9.2)

  • Sex (M/F): all male

  • Exclusion criteria: primary hyperparathyroidism, primary hyperoxaluria, enteric hyperoxaluria, bowel resection, inflammatory bowel disease, renal tubular acidosis, sarcoidosis, or sponge kidney

Interventions

Treatment group 1

  • Low calcium diet: 10 mmol/d

  • Water intake: 2 to 3 L/d

Treatment group 2

  • Normal-to-high intake of calcium: 30 mmol/d

  • Low protein diet: < 15% of total energy

  • Low salt diet: < 50 mmol/d

  • Water intake: 2 to 3 L/d

Outcomes
  • Stone formation: time to first symptomatic or radiographically identified stone

  • Changes in calcium and oxalate excretion, calcium oxalate product, and relative calcium oxalate saturation

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation generated by an investigator. Random number sequence (odd number group A and even number group B)
Allocation concealment (selection bias)Low riskRandom number sequence enclosed in sealed, numbered envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskDue to the nature of the intervention, patients and researchers were not blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs reported: 17 did not complete the study: 9 patients in Group A (hypertension (7) died (2)); 8 in Group B (hypertension (1), gout (1), embolism (1), lost to follow-up (2), withdrew consent (3))
Selective reporting (reporting bias)Low riskFree of suggestion of selective outcome reporting
Other biasLow riskApparently free of other problems that could put it at a risk of bias

Coe 1992

Methods
  • Study design: cross-over RCT. Two treatment phases 28 days in length (periods I and 2), 2, 7-day baseline periods and a 7-day washout period at the start of the study and again between treatments

  • Time frame: NS

  • Study duration: 76 days

Participants
  • Setting: single centre

  • Country: USA

  • Healthy, relatives of hypercalciuric stone-forming patients, without any clinical manifestation

  • Number: 12

  • Age 18 to 30 years

  • Sex (M/F): 6/6

  • Exclusion criteria: NS

Interventions

Treatment group 1

  • 2% milk: 2 x 8 oz glasses/d

Treatment group 2

  • Orange juice + calcium citrate malate salt supplement: 2 x 6 oz glasses/d (calcium supplement: 600 mg/d)

Outcomes
  • Reduction in 24 h urine calciuria and oxaluria

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation method not described
Allocation concealment (selection bias)Unclear riskAllocation concealment not described
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding of intervention and outcome measurement
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not specified
Selective reporting (reporting bias)Low riskApparently free of selective outcome reporting
Other biasLow riskApparently free of other factors that could influence bias

Gleeson 1990

Methods
  • Study design: parallel RCT

  • Time frame: NS

  • Study duration: 3 weeks

Participants
  • Setting: single centre

  • Country: USA

  • Patients with a previous history of renal calculus formation and know hypercalciuria (> 200 mg/d)

  • Number: treatment group (9); control group (8)

  • Age range: 39 to 65 years

  • Sex (M/F): 16/1

  • Exclusion criteria: NS

Interventions

Treatment group

  • Calcium (301 mg) and oxalate (202 mg) diet

  • Unprocessed wheat bran: 78.2 g

Control group

  • Calcium (370 mg) and oxalate (38 mg) diet

Pharmacological co-intervention with hydrochlorothiazide (50 µg/12 h) + potassium citrate (5 mEq/8 h) in both groups

Outcomes
  • Reduction in 24 h urine calciuria and oxaluria

Notes
  • Drop-outs: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation method not described
Allocation concealment (selection bias)Unclear riskAllocation method unspecified
Blinding (performance bias and detection bias)
All outcomes
High riskDue to the nature of the intervention, patients and researchers were not blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not specified
Selective reporting (reporting bias)Low riskApparently free of selective outcome reporting
Other biasHigh riskPharmacological co-intervention with hydrochlorothiazide (50 µg/12 h) + potassium citrate (5 mEq/8 h) in both groups

Nishiura 2004

Methods
  • Study design: parallel RCT

  • Time frame: NS

  • Study duration: 3 months

Participants
  • Setting: Single centre

  • Country: Brazil

  • Patients with at least one kidney stone

  • Number: treatment group (33); control group (36)

  • Mean age ± SD (years): treatment group (39 ± 9); control group (37 ± 8)

  • Sex (M/F): treatment group (17/16); control group (22/14)

  • Exclusion criteria: patients with diseases that might have led to secondary calcium stones, such as primary hyperparathyroidism, distal renal tubular acidosis, UTIs, primary hyperoxaluria

Interventions

Treatment group

  • Phyllanthus niruri capsules: 450 mg, 3 times/d

Control group

  • Chicorium sativum capsules: 450 mg, 3 times/d

Co-interventions: NS

Outcomes
  • Reduction in calciuria (24 h urine calciuria or calcium/creatinine ratio)

Notes
  • Dropouts: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation method unspecified
Allocation concealment (selection bias)Unclear riskAllocation method unspecified
Blinding (performance bias and detection bias)
All outcomes
Low risk P. niruri and placebo capsules were manufactured in the same way
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts not reported
Selective reporting (reporting bias)Low riskApparently free of selective outcome reporting
Other biasUnclear riskPossible differences in co-intervention between groups not excluded

Nouvenne 2010

  1. a

    NS - not stated; UTI - urinary tract infection

Methods
  • Study design: parallel RCT, stratified according to sex

  • Time frame: January 2005 to December 2007

  • Study duration: 3 months

Participants
  • Setting:

  • Country: Italy

  • Patients with hypercalciuria, with at least one oxalate calcium stone excretion episode

  • Number: treatment group (108); control group (102)

  • Mean age ± SD (years): treatment group (39 ± 9); control group (40 ± 10)

  • Sex (M/F): treatment group (78/30); control group (72/30)

  • Exclusion criteria: primary hyperparathyroidism, primary hyperoxaluria, enteric hyperoxaluria, bowel resection, inflammatory bowel disease, renal tubular acidosis, sarcoidosis, sponge kidney, and hyperthyroidism; chronic use of drugs capable of increasing the risk of calcium stone formation, such as vitamin D, acetazolamide, and antiepileptic drugs

Interventions

Treatment group

  • Low salt diet: no salt used in cooking or added to foods

  • Water: 2 to 3 L/d

  • Calcium: normal levels (800 to 100 mg/d)

Control group

  • Water: 2 to 3 L/d

Outcomes
  • Reduction in 24 h urine calciuria and oxaluria

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated 2 sequences of random treatment assignments. Randomisation was stratified according to sex
Allocation concealment (selection bias)Low riskTreatment assignment was concealed from the doctor and the patient by using 2 series of sealed, progressively numbered envelopes for men and women
Blinding (performance bias and detection bias)
All outcomes
High riskDue to the nature of the intervention, patients and researchers were not blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk13 participants did not complete the study: 2 patients in Group A (due to work problems to assist visits) and 11 patients in Group B (due to adaptation problems to low salt diet)
Selective reporting (reporting bias)Low riskApparently free of selective outcome reporting
Other biasHigh riskStudy findings applicable only to patients used to high salt diets (averaging up to 13 g/d)

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ala-Opas 1987Wrong intervention: patients treated with thiazides
Aras 2008Wrong population: study performed in patients with hypocitraturia
Baxmann 2003Wrong population: no patients with hypercalciuria included
Bellizzi 1999Wrong population: no patients with hypercalciuria included
Borghi 1996No data analysis of hypercalciuria group participants
Campoy Martinez 1994No data analysis of hypercalciuria group participants
Colette 1993Not RCT
Domrongkitchaiporn 2004Wrong population: no patients with hypercalciuria included
Hiatt 1996No data analysis of hypercalciuria group participants. Patients had histories of recurrent calcium oxalate kidney stones. RCT evaluated effects of low animal protein/high fibre diet plus fluid and calcium intake recommendations versus fluid and calcium intake recommendations alone
Jaeger 1982Not RCT
Karagulle 2007No data analysis of hypercalciuria group participants
Kocvara 1999No data analysis of hypercalciuria group participants
Lamid 1984Wrong population: study performed in spinal cord injury patients
Matsumoto 2006Wrong population: no patients with hypercalciuria
Muller 2001Not RCT
Rotily 2000No data analysis of hypercalciuria group participants
Schwille 1997Not RCT
van Faassen 1998Data not provided on each group at the end of the intervention; intra-group differences reported from baseline only

Ancillary