Dietary interventions for preventing complications in idiopathic hypercalciuria
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
‐ To assess the efficacy, effectiveness and safety of dietary interventions for preventing complications in IH (urolithiasis and osteopenia).
‐ To assess the benefits of dietary interventions in decreasing urological symptomatology in children with IH.
Background
Idiopathic hypercalciuria (IH) is defined as urinary excretion of more than 250 mg calcium/day for women or more than 275‐300 mg calcium/day for men while on a regular, unrestricted diet and with no evidence of secondary causes (i.e. primary hyperparathyroidism, renal tubular acidosis, malignancy, vitamin D intoxication, immobilization, hyperthyroidism and Bartter's syndrome) (Langman 1984). It can also be defined as the excretion of urinary calcium in excess of 4 mg/kg body weight/day in children. IH is one of the most common hereditary metabolic anomalies, with prevalence rates in the healthy population reported to be between 2.9% and 6.5% (García‐Nieto 2000).
The physiopathology of IH is highly complex. Hypercalciuria has been attributed to numerous factors that affect the calcium‐phosphorus metabolism. There are three main physiopathological mechanisms: 1) reduction in the tubular reabsorption of calcium, with the emergence of compensatory hyperparathyroidism (Coe 1973); 2) an increase in, or hypersensitivity to, the intestinal reabsorption of calcium secondary to high levels of calcitriol (Pak 1979); and 3) renal loss of phosphates with secondary increased synthesis of calcitriol and intestinal hyperabsorption (Navarro 1994). When concentrations of calcium and oxalate reach saturation, stones begin to form with the association of small amounts of crystalloid that form nuclei. These nuclei normally grow and aggregate on surfaces such as collecting ducts and renal papillary epithelium. Fortunately, stone formation is inhibited in urine by substances that prevent crystallisation (magnesium, citrate, pyrophosphate). Therefore, crystallisation in undiluted human urine will begin only in a supersaturated solution of calcium and oxalate. About 80% of all kidney stones contain calcium, and at least 40% to 60% of all calcium stone formers are found to have hypercalciuria when tested (Lerolle 2002). Hypercalciuria contributes to kidney stone disease in adults and children (Stapleton 1987). In industrialised nations, renal stones occur in 15% of men and 6% of women and recur in approximately half (Bihl 2001).
The morbidity of urinary tract calculi is primarily due to obstruction with associated pain, although it is well recognized that non‐obstructing calculi can still produce considerable discomfort. On the other hand, obstructing calculi can be asymptomatic, which is the typical scenario in the unusual patient who suffers renal loss from chronic, untreated obstruction. Haematuria caused by stones, while frightening to the patient, is rarely dangerous in itself. In children, hypercalciuria can cause a wide variety of symptoms, the most common of which is recurrent haematuria (macroscopic or microscopic). Haematuria is thought to be caused when calcium oxalate injures the uro‐endothelium: it is self‐limited and it is not accompanied by proteinuria (García 1991). Other common clinical manifestations are frequency‐dysuria syndrome and abdominal and lumbar pain. Its association with recurrent urinary infections has also been described (Vachvanich 2001). The most morbid and potentially dangerous aspect of stone disease is the combination of obstruction and infection of the upper urinary tract. Pyelonephritis, pyonephrosis (gross pus in the renal collecting system) and urosepsis can result (Leslie 2000).
Another problem with hypercalciuria is its possible relationship with osteopenia and osteoporosis, especially when due to renal‐leak hypercalciuria. The extra calcium required for renal excretion is drawn from the bones and eventually reduces bone density (Asplin 2003; Freundlich 2002). Up to 30% of children with IH have osteopenia, the long‐term seriousness of which has yet to be determined (García‐Nieto 1997).
Various dietary interventions have traditionally been suggested for patients with idiopathic hypercalciuria, particularly if it is accompanied by lithiasis (Rodgers 2002). Increasing the intake of liquids is one of the most general recommendations. Plentiful water or liquids may decrease urinary supersaturation and protect against the formation of calculi. Curhan's extensive observational study supported this possibility (Curhan 1998). Qiang's systematic review showed that increasing the intake of water prevented the risk of recurrence in populations with any sort of urinary calculus, although he found no evidence (through lack of RCTs) that this measure was of any benefit in primary prevention (Qiang 2004).
Reducing calcium intake is another common recommendation, but it seems that this may not be appropriate. It has even been suggested that calcium in the diet prevents the excessive absorption of oxalate in the digestive tract. Therefore, the intake of moderate amounts of calcium (e.g. 600‐800 mg/day) could be beneficial because it would reduce oxaluria and minimise the risk of osteopenia. On the other hand, excessive amounts (e.g. above 2000 mg) could annul the supposedly protective effect on the absorption of oxalate and promote hypercalcemia, hypercalciuria and the formation of calculi (Bataille 1983; Coe 1982; Curhan 1997b; Fuss 1990; Harward 1993; Lemann 1996).
A high consumption of animal proteins may have several negative effects on hypercalciuric patients. Firstly, it could cause an acid overload, which would inhibit the renal reabsorption of calcium and increase its urinary excretion. Whats more, an excess of acid may be neutralised, at least partly, by the release of skeletal calcium phosphate into the general circulation, which would contribute to the increase in hypercalciuria. Secondly, when these proteins are metabolised, purines are generated which, as precursors of uric acid, increase its plasma levels. This increase facilitates the formation of uric acid lithiasis and contributes to the excess of acid that finally favours the excretion of urinary calcium. Although Curhan's observational studies (Curhan 1993) showed a certain correlation between a high intake of proteins and a greater risk of lithiasis, a clinical trial carried out by Hiatt 1996 comparing a high intake of water with a protein‐poor diet showed that the protective effect of the diet was small (Breslau 1988; Curhan 1993; Curhan 1997a; Liatsikos 1999). Evaluating the effect of dietary intervention on urinary risk factors for recurrence in calcium oxalate stone formers, Siener 2005 identified a low fluid intake and an increased intake of protein and alcohol as the most important dietary risk factors. The shift to a nutritionally balanced diet according to the recommendations for calcium oxalate stone formers significantly reduced the stone forming potential.
Since the oxalate in the diet is responsible for approximately 80% of all urinary oxalate, it has been suggested that restricting it could be a protective factor. However, observational studies in this area have been controversial (Assimos 2000). Those subjects with high intakes of ascorbic acid have high excretions of oxalate, but they have not been found to have greater lithiasis (Curhan 1999).
A high sodium intake has also been related to a risk of hypercalciuria and the formation of calculi. It has been suggested that some of the mechanisms involved are that the release of bone calcium increases when salt intake is greater, and the direct effect of sodium on the kidney increases the excretion of calcium. Salt restriction has been correlated with a decrease in calciuria levels in patients with hypercalciuria (Breslau 1982; Martini 2000; Muldowney 1982; Sakhaee 1993).
In a population of susceptible subjects, a relatively low intake of potassium may promote the formation of calculi. This effect has been attributed to an increase in calciuria and a decrease in the excretion of urinary citrate (Curhan 1993; Heilberg 2000).
Certain lifestyles can affect the onset of pathologies secondary to hypercalciuria, particularly the consumption of alcohol and coffee. Ethanol seems to decrease osteoblastic activity and parathormone (PTH) levels, and increase the urinary excretion of calcium. All this could favour osteoporosis (de Vernejoul 1983; García‐Sánchez 1995). The excessive consumption of coffee has also been related to increases in calcium excretion (Morgan 1994). In a population that is susceptible to lithiasis, restrictions in the intake of soft drinks acidified with phosphoric acid could lead to a decrease in the incidence of lithiasis (Shuster 1992). Some plant infusions have been thought to decrease the recurrence of lithiasis in populations that are not specifically hypercalciuric (Premgamone 2001). Likewise, some fruit juices (e.g. cranberry) may be protective (McHarg 2003). Grapefruit juice, however, for reasons that have not been fully explained, has been associated with an increase in risk of lithiasis in two cohort studies from a population that was not specifically hypercalciuric (Curhan 1996; Curhan 1998).
Other dietary interventions that may be of some interest are the limitation of refined carbohydrates, which may favour intestinal calcium absorption, and the consumption of fibre which bonds to the free calcium in the intestinal lumen and may decrease its absorption. (Ebisuno 1986; Jahnen 1992).
One problem most studies analysing the effectiveness of dietary interventions on renal lithiasis must deal with is that the course of the disease is slow and variable. The average rate of stone formation in recurrent stone formers is approximately 0.15 to 0.20 stones/year (Tiselius 2000). This means that any study that attempts to demonstrate the efficacy of specific treatment programmes must last for several years.
Objectives
‐ To assess the efficacy, effectiveness and safety of dietary interventions for preventing complications in IH (urolithiasis and osteopenia).
‐ To assess the benefits of dietary interventions in decreasing urological symptomatology in children with IH.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐RCTs (e.g. allocation using alternative, case record numbers, date of birth or day of the week) that compare the efficacy of dietary interventions for preventing complications in IH.
Types of participants
Inclusion criteria
Studies performed on hypercalciuric male and female patients (adults or children), stone and non‐stone formers, in whom diet was introduced to decrease the risk of recurrence of stones, to prevent stone formation and to eliminate symptoms (dysuria, haematuria, abdominal pain).
Exclusion criteria
Studies on/including patients with secondary hypercalciuria or suffering other illnesses that could cause osteopenia or urolithiasis.
Types of interventions
Studies testing any dietary intervention for preventing complications in IH, comparing it to placebo, no interventions, other dietary intervention or a different administration mode or amount of the same treatment.
We shall assess only those interventions that have a minimum duration of one year.
Types of outcome measures
Primary outcomes
‐ Reduction in stone formation (stone rate or calcium stone recurrences or increase in calculi‐free patients). Stone rate is defined as the number of stones/patient/year over a minimum of three years. A new stone is defined by radiography, ultrasonography or pyelography as all patients were calculi‐free before therapy.
‐ Increase or no reduction in bone mass: Dual‐energy X‐ray, absorptiometry over a minimum of one year.
‐ Reduction in urinary symptoms (incidence of urinary tract infections (UTI), haematuria, dysuria, enuresis) in children over a minimum of one year.
‐ Improvement in quality of life in terms of days in hospital, days off work or days off school.
Secondary outcomes
‐ Reduction in calciuria (decrease in 24‐hour calciuria or urinary calcium/creatinine ratio)
‐ Reduction in creatinine clearance
Adverse clinical reactions
‐ 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
Relevant trials will be obtained from the following sources:
1). Cochrane Renal Group's specialised register and Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library ‐ most recent) which will be searched using the following terms:‐
#1. Kidney Diseases, this term only in MeSH
#2. Ureteral Diseases explode all trees in MeSH
#3. (#1 OR #2)
#4. Colic explode all trees in MeSH
#5. (#3 AND #4)
#6. Urinary Calculi explode all trees in MeSH
#7. Ureteral Obstruction, this term only in MeSH
#8. urolithiasis in All Fields
#9. ureterolithiasis in All Fields in all products
#10. nephrolithiasis in All Fields in all products
#11. ureter next (stone* or calcul* or colic* or lithiasis) in All Fields
#12. kidney next (stone* or calcul* or colic* or lithiasis) in All Fields
#13. renal next (stone* or calcul* or colic* or lithiasis) in All Fields
#14. urin* near (stone* or calcul* or colic* or lithiasis) in All Fields
#15. (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14)
#16. calcium in All Fields
#17. (#15 AND #16)
#18. hypercalciuria in All Fields
#19. Calcium, this term only with qualifier: UR in MeSH
#20. Calcium, this term only in MeSH
#21. Urine, this term only in MeSH
#22. (#20 AND #21)
#23. renal tubular absorpt* and calcium in All Fields
#24. (#18 OR #19 OR #22 OR #23)
#25. (#17 OR #24)
2). MEDLINE (1966 to most recent) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of randomised controlled trials (Dickersin 1994) with a specific search strategy for "Pharmacological interventions for preventing complications in idiopathic hypercalciuria" developed with input from the Cochrane Renal Group Trial Search Coordinator.
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized controlled trials/
4. random allocation/
5. double blind method/
6. single blind method/
7. or/1‐6
8. animals/ not (animals/ and human/)
9. 7 not 8
10. clinical trial.pt.
11. exp clinical trials/
12. (clinic$ adj25 trial$).ti,ab.
13. cross‐over studies/
14. (crossover or cross‐over or cross over).tw.
15. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
16. placebos/
17. placebo$.ti,ab.
18. random$.ti,ab.
19. research design/
20. or/10‐19
21. 20 not 8
22. 9 or 21
23. kidney diseases/
24. exp ureteral diseases/
25. colic/
26. (23 or 24) and 25
27. exp Urinary Calculi/
28. urolithiasis.tw.
29. ureterolithiasis.tw.
30. nephrolithiasis.tw.
31. (ureter$ stone$ or ureter$ calcul$ or ureter$ colic).tw.
32. (kidney stone$ or kidney calcul$ or kidney colic).tw.
33. (renal stone$ or renal calcul$ or renal colic).tw.
34. (urin$ adj3 (stone$ or calcul$ or colic)).tw.
35. or/26‐34
36. calcium.af.
37. 35 and 36
38. hypercalciuria.tw.
39. calcium/ur
40. calcium/ and urine/
41. renal tubular reabsorption.tw. and calcium.af.
42. or/37‐41
43. 22 and 42
3). EMBASE (1980 to most recent) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of randomised controlled clinical trials (Lefebvre 1996) together with a specific search strategy developed with input from the Cochrane Renal Group Trial Search Coordinator.
1. Idiopathic Hypercalciuria/
2. hypercalciuria$.tw.
3. or/1‐2
4. exp clinical trial/
5. evidence based medicine/
6. outcomes research/
7. crossover procedure/
8. double blind procedure/
9. single blind procedure/
10. prospective study/
11. major clinical study/
12. exp comparative study/
13. placebo/
14. "evaluation and follow up"/
15. follow up/
16. randomization/
17. or/4‐16
18. controlled study/ not case control study/
19. or/17‐18
20. (clinic$ adj5 trial$).ti,ab.
21. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
22. random$.ti,ab.
23. placebo$.ti,ab.
24. or/20‐23
25. 19 or 24
26. limit 25 to human
27. and/3,26
4). Reference lists of nephrology textbooks, review articles and relevant trials and conference proceedings.
5). Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.
Data collection and analysis
Included and excluded studies
The review will be undertaken by five reviewers (JE, AB, FP, MR and AF). The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by the reviewers, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. All reviewers will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Data extraction will be carried out by the all the same reviewers independently using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one trial exists, only the publication with the most complete data will be included. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved in consultation with MR.
Study quality
The quality of studies to be included will be assessed independently by JE, AB, FP and AF without blinding to authorship or journal using the checklist developed for the Cochrane Renal Group. Discrepancies will be resolved by discussion with MR. The quality items to be assessed are allocation concealment, intention‐to‐treat analysis, completeness to follow‐up and blinding of investigators, participants and outcome assessors.
Quality checklist
1. Allocation concealment
A. Adequate ‐ Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
B. Unclear ‐ Randomisation stated but no information on method used is available
C. Inadequate ‐ Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group.
2. Blinding
Blinding of investigators: Yes/No/not stated
Blinding of participants: Yes/No/not stated
Blinding of outcome assessor: Yes/No/not stated
Blinding of data analysis: Yes/No/not stated
The above are considered not blinded if the treatment group can be identified in > 20% of participants because of the side effects of treatment.
3. Intention‐to‐treat analysis
Yes ‐ Specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.
Yes ‐ not specifically reported but confirmed upon study assessment
No ‐ Not reported and lack of intention‐to‐treat analysis confirmed on study assessment. (Patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation)
No ‐ Stated but not confirmed upon study assessment
Not stated
4. Completeness to follow‐up
Per cent of participants excluded or lost to follow‐up (because of adverse effects of intervention or patients leave the study).
Statistical assessment
For dichotomous outcomes (new stones, osteopenia, haematuria, frequency‐dysuria syndrome,UTI, gastrointestinal side effects) results will be expressed as relative risk (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are 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 weighted mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.
Data will be pooled using the random effects model but the fixed effects model will also be analysed to ensure robustness of the model chosen. Heterogeneity will be analysed using a Chi squared test on N‐1 degrees of freedom, with an alpha of P‐value of 0.10 used for statistical significance and with the I2 test (Higgins 2003).
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, treatments and study quality). Heterogeneity among participants could be related to age and renal pathology. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
If sufficient RCTs are identified, an attempt will be made to examine for publication bias using a funnel plot (Egger 1997).
