Pharmacological 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 pharmacological interventions for preventing complications in IH (urolithiasis and osteopenia).
‐ To assess the benefits of pharmacological interventions in decreasing urological symptomatology in children with IH.
Background
Idiopathic hypercalciuria (IH) is defined as calcium excretion greater than 0.1 mmol/kg/24 h in patients with an unrestricted calcium diet and with no evidence of secondary causes, such as primary hyperparathyroidism, renal tubular acidosis, malignancy, vitamin D intoxication, immobilization, hyperthyroidism and Bartter's syndrome (Langman 1984). IH is one of the most common hereditary metabolic anomalies, to such an extent that prevalence rates in the healthy population have been 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 theassociation 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 40‐60% 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 (Garcia 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 ensue (Leslie 2000).
Another problem with hypercalciuria is its possible relationship with osteopenia and osteoporosis, especially when due to renal‐leak hypercalciuria. The extra calcium requiredfor 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 (Garcia‐Nieto 1997). Numerous pharmacological treatments have been described that can decrease levels of calciuria or its index of urinary crystallization, although its real role in controlling the illness and preventing its clinical manifestations is controversial. Thiazide has been shown to correct the renal‐leak of calcium by increasing calcium reabsorption in the distal tubule, depleting extracellular volume and stimulating calcium reabsorption in the proximal tubule.
Many studies have analysed how efficient diuretics are at preventing the recurrence of idiopathic calcium stones, although very few have focused on patients with proven hypercalciuria (Pearle 1999). As the substrate of most calcium lithiases is hypercalciuria, it may be possible to extrapolate some of the results, although further in‐depth studies are required. Thiazides can cause hypokaliaemia, which in turn leads to the appearance of intracellular metabolic acidosis and hypocitraturia. Indapamide, a non‐thiazide diuretic, seems to have similar effects, although with fewer side effects (Borghi 1993). Thiazides have been shown to be useful for recovering bone mass in patients with recurrent lithiasis and hypercalciuria, although the long‐term effect of this pharmacological measure is still not very clear.
Potassium citrate has an inhibitory activity on calcium oxalate, crystallization, aggregation and agglomeration and it has given good results in patients with hypocitraturia (Barcelo 1993). A new salt, magnesium/potassium citrate, seems to be effective at decreasing the recurrence of calcium lithiases in patients with no specific metabolic disorder (Ettinger 1997). Its possible beneficial effect on recovering bone mass is not clear. Allopurinol, a xanthine oxidase inhibitor, reduces uric acid synthesis and lowers urinary uric acid. It has proven to be effective at reducing the recurrence of calcium lithiasis only in those patients with marked hyperuricosuria and normocalciuria, but not in those with non‐specific calcium lithiasis or with hypercalciuria (Ettinger 1986; Wilson 1984).
Orthophosphates reduce vitamin D levels, which leads to a subsequent reduction in urinary calcium excretion. They also increase urinary levels of pyrophosphate and citrate, which increases the inhibitory capacity. Despite these properties, the studies have not been able to show conclusively any beneficial effect on the recurrence of lithiasis. Their theoretical benefit on the recovery of bone mass is not conclusive either (Breslau 1995; Ettinger 1976; Ulmann 1984). Such other drugs as bisphosphonates (Bushinsky 1999; Ruml 1995), sodium cellulose phosphate (Hayashi 1975), and dipyridamole (Michaut 1994) have either not been shown to be effective at preventing lithiasis or have considerable adverse effects.
One problem that most studies that analyse the effectiveness of drug treatments 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 stone/year (Tiselius 2000). This means that a study that attempts to demonstrate the efficacy of specific treatment programmes must last for some years.
Objectives
‐ To assess the efficacy, effectiveness and safety of pharmacological interventions for preventing complications in IH (urolithiasis and osteopenia).
‐ To assess the benefits of pharmacological 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 pharmacological interventions at preventing complications in IH.
Types of participants
Inclusion criteria
Studies performed on adult patients and children with IH undergoing pharmacological treatment to control the illness and its complications.
Exclusion criteria
Studies on/including patients with secondary hypercalciurias or suffering other illnesses that could cause osteopenia or urolithiasis.
Types of interventions
Studies testing any pharmacological intervention for preventing complications in IH, comparing it to placebo, other pharmacological intervention or a different administration mode or dose of the same treatment.
We shall assess only those interventions that have a minimum duration of one year.
Types of outcome measures
Primary outcomes
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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 per patient per year over a minimum of 3 years.A new stone is defined by radiography, ultrasonography or pyelography as all patients were calculi‐free before therapy.
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Increase or no reduction in bone mass: Dual‐energy X‐ray, absorptiometry over a minimum of one year
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Reduction in urinary symptoms (incidence of urinary tract infections, hematuria, dysuria, enuresis) in children over a minimum of one year
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mprovement in quality of life in terms of days in hospital, days off work or days off school
Secondary outcomes
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Reduction in calciuria (decrease in 24‐hour calciuria or urinary calcium/creatinine ratio)
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Reduction in creatinine clearance
Adverse clinical reactions
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Gastrointestinal side effects
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Increased levels of cholesterol and triglycerides
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Changes in blood pressure
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Reduction in serum 1,25‐dihydroxyvitamin
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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
2. Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library ‐ most recent) which will be searched using the following terms:‐
#1 Hypercalciuria
#2 Calculi, Urinary. Explode tree Mesh
#3 Urinary and (Ston$ or calcul$)
#4 Urolithiasis
#5 Treatment (MeSH)
#6 Drug Therapy (MeSH)
#7 Prevention or Prophylaxis(MeSH)
#8 (#1 or #2 or #3 or #4) and (#5 or #6 or #7)
3. MEDLINE using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of randomised controlled trials (Dickersin 1994) with a specific search strategy for "Pharmacological interventions for preventing complications in idiopathic hypercalciuria" developed with input from the Cochrane Renal Group Trial Search Coordinators.
MEDLINE search strategy (1966 to most recent): 2003
1 RANDOMISED CONTROLLED TRIAL. pt.
2 CONTROLLED CLINICAL TRIAL. pt.
3 RANDOMIZED CONTROLLED TRIALS/
4 RANDOM ALLOCATION/
5 DOUBLE BLIND METHOD/
6 SINGLE BLIND METHOD/
7 1 or 2 or 3 or 4 or 5 or 6
8 ANIMAL/ not HUMAN/
9 7 not 8
10 CLINICAL TRIAL. pt.
11 exp CLINICAL TRIALS/
12 (clin$ adj25 trial$).tw.
13 CROSS‐OVER STUDIES/
14 (crossover or cross‐over or cross over).tw.
15 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).tw.
16 PLACEBOS/
17 placebo$.tw.
18 random$.tw.
19 RESEARCH DESIGN/
20 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21 20 not 8
22 9 or 21
23 Hypercalciuria.tw.
24 exp Calculi, Urinary/
25 (Urinary and (Ston$ or calcul$)).tw.
26 Urolithiasis.tw.
27 Treatment/
28 Drug Therapy/
29 Prevention/ or Prophylaxis
30 (23 or 24 or 25 or 26) and (27 or 28 or 29)
31 30 and 22
4. EMBASE 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 Coordinators.
5. Reference lists of nephrology textbooks, review articles and relevant trials.
6. Reference lists of abstracts from nephrology scientific meetings.
7. 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 four reviewers (JE, AB, FP 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. 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 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
Statistical assessment
For dichotomous outcomes (new stones, osteopenia, hematuria, frequency‐dysuria syndrome, urinary tract infection, gastrointestinal side effects) results will be expressed as relative risk (RR) with 95% confidence intervals (CI). 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 and susceptibility to outliers. 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, serum cholesterol and triglycerides, serum 1,25‐dihydroxy D vitamin, natraemia, calcaemia, uricaemia, calami, magnesaemia, chloraemia, acidosis, glycaemia, oxaluria and citraturia), the weighted mean difference (WMD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a Chi squared test on N‐1 degrees of freedom, with an a of p‐value of 0.10 used for statistical significance.
Sensibility 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).
