n e f r o l o g i a 2 0 2 2;4 2(5):506–518 Revista de la Sociedad Española de Nefrología www.revistanefrologia.com Review Pharmacological interventions for preventing complications in patients with idiopathic hypercalciuria: A systematic review Natalia Ferre a , Ester Parada a,b , Albert Balaguer c,d , Albert Feliu a,e , Marta Roqué-Figuls f , Juan Victor A. Franco g , Joaquín Escribano a,e,∗ a Universitat Rovira i Virgili, School of Medicine, Pediatric Research Unit, Sant Llorenç 21, 43201 Reus, Spain b Department of Pediatrics, Hospital Universitari de Tarragona Joan XXIII, Dr. Mallafré Guasch 4, 43005 Tarragona, Spain c Department of Pediatrics, Hospital Universitari General de Catalunya, Pere i Pons 1, 08195 Sant Cugat del Vallés, Barcelona, Spain d Universitat Internacional de Catalunya, Carrer de la Immaculada 22, 08017 Barcelona, Spain e Department of Pediatrics, Hospital Universitari St Joan de Reus, Avinguda del Doctor Josep Laporte 2, 43204 Reus, Spain f Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP), Sant Quintí 77-79, 08041 Barcelona, Spain g Argentine Cochrane Centre, Instituto Universitario Hospital Italiano, Potosí 4265, C1199 CABA Buenos Aires, Argentina a r t i c l e i n f o a b s t r a c t Keywords: Objective: To assess the effects of pharmacological interventions in patients with idiopathic Idiopathic hypercalciuria hypercalciuria. Diuretics Methods: We performed a search of multiple databases, trial registries, grey literature and Kidney stones conference proceedings up to October 2019. We included randomized and quasi-randomized Systematic review controlled trials that examined any pharmacological intervention for preventing complica- tions of idiopathic hypercalciuria (given for at least four months and six of follow-up). The primary outcomes were stone-free patients, urinary symptoms and severe adverse events. Results: We included five RCTs (n = 446 patients, all adults, 4 in individuals with kidney stones and 1 in postmenopausal women with osteoporosis). Diuretics were likely to increase the number of stone-free patients (RR 1.61, 95% CI 1.33–1.96, moderate quality of evidence (QoE)); 274 more stone-free patients/1000 patients treated (95% CI: 148–432) and produced a slight decrease in the stone formation rate (mean difference −0.18, 95% CI −0.30 to −0.06, low QoE); 180 fewer stones/year/1000 patients treated (95% CI: 300 r to 60). No data on urinary symptoms were reported. The association between diuretic use and severe adverse events was uncertain (RR 5.00, 95% CI 0.60–41.88, very low QoE); 4 more severe adverse events/1000 patients treated (95% CI: 0 fewer to 39 more). Abbreviations: BMD, bone mineral density; CI, confidence interval; IH, idiopathic hypercalciuria; SD, standard deviation; QoE, quality of evidence; RCT, randomized clinical trial; RR, relative risk. ∗ Corresponding author. E-mail address: joaquin.escribano@urv.cat (J. Escribano). https://doi.org/10.1016/j.nefro.2021.04.007 http://dx.doi.org/10.1016/j.nefroe.2021.04.014 2013-2514 0211-6995/© 2021 Sociedad Española de Nefrologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). n e f r o l o g i a 2 0 2 2;4 2(5):506–518 507 Conclusions: The addition of diuretics to a normal or modified diet probably reduces the number of stone recurrences and may decrease the stone formation rate. It is uncertain whether diuretics increase the occurrence of severe adverse events. There were no studies investigating other outcomes or in children. © 2021 Sociedad Española de Nefrologı́a. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). Intervenciones farmacológicas para prevenir complicaciones en pacientes con hipercalciuria idiopática: una revisión sistemática r e s u m e n Palabras clave: Objetivo: Evaluar los efectos de intervenciones farmacológicas en pacientes con hipercalci- Hipercaliuria idiopática uria idiopática. Diuréticos, Cálculos renales Métodos: Realizamos una búsqueda en múltiples bases de datos, registros de ensayos, Revisión sistemática literatura gris y actas de congresos hasta octubre de 2019. Incluimos ensayos clínicos aleator- izados y cuasialeatorizados que examinaban cualquier intervención farmacológica para prevenir las complicaciones de la hipercalciuria idiopática (mínimo 4 meses de interven- ción y 6 meses de seguimiento). Los outcomes primarios fueron pacientes libres de cálculos, síntomas urinarios y efectos adversos graves. Resultados: Incluimos 5 RCT (n = 446 pacientes, todos adultos, 4 en individuos con cálculos renales y uno en mujeres posmenopáusicas con osteoporosis). Los diuréticos aumentaban probablemente el número de pacientes libres de cálculos (RR 1,61; IC 95%: 1,33 a 1,96, moder- ada calidad de evidencia [QoE]); 274 más pacientes libres de cálculos/1.000 pacientes tratados (IC 95%: 148 a 432) y producían una ligera disminución en la tasa de formación de cálcu- los (diferencia media −0,18; IC 95%: −0,30 a −0,06, baja QoE); 180 menos cálculos/año/1.000 pacientes tratados (IC 95%: 300 a 60). No se informaron datos sobre síntomas urinarios. La asociación entre el uso de diuréticos y los efectos adversos graves fue incierta (RR 5,00; IC 95%: 0,60 a 41,88, muy baja QoE); 4 efectos adversos severos más/1.000 pacientes tratados (IC 95%: 0 a 39). Conclusiones: Los diuréticos añadidos a una dieta normal o modificada probablemente reducen la aparición de cálculos y pueden disminuir su tasa de formación. Es incierto si los diuréticos incrementan la ocurrencia de efectos adversos graves. No se encontraron estudios que investigaran otros outcomes o realizados en niños. © 2021 Sociedad Española de Nefrologı́a. Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/ by-nc-nd/4.0/). related with an increase of vitamin D receptors (observed in Introduction the gut and bone of IH rats as well as in monocytes from both rats and humans) and/or a raise in the functional activity of Idiopathic hypercalciuria (IH), one of the most common hered- the calcitriol-VDR complexes that induced an increase in both itary metabolic anomalies, is defined as calcium excretion intestinal calcium absorption and bone resorption.5 greater than 300 mg/24 h in men and 250 mg/day in women; One of the undesired consequences of IH is stone forma- it is also defined as Ca urine > 4 mg/kg (body weight) or tion that starts when concentrations of calcium and oxalate Ca/Creatinine > 0.20 mg/mg among patients of both sexes with reach saturation. Approximately 80% of all kidney stones con- an unrestricted calcium diet and no evidence of secondary tain calcium, and at least 40–60% of all patients who form causes.1 Prevalence rates ranging from 2.9% to 22% have been calcium stones are found to have hypercalciuria when tested.6 reported in the healthy population.2,3 Therefore, hypercalciuria contributes to kidney stone disease The pathophysiology of IH is highly complex. There are in adults and children.7 three main pathophysiological mechanisms: reduced tubular The reported prevalence of renal stones in different coun- reabsorption, increased intestinal absorption and increased tries and over time is highly variable, ranging from 1.7% bone resorption. However, there are several interrelationships to 18.5%,8 and recurrence is approximately 50%.9 Diverse between all these mechanisms as well as with diet factors and morbidity manifestations such as obstruction, haematuria, most patients manifest different features belonging to more frequency-dysuria syndrome, abdominal and lumbar pain, than one mechanism.4 As an example of this interrelation- and recurrent urinary infections10 are related to urolithiasis. ships, there is evidence that one IH development could be The potentially most dangerous aspect of stone disease is the 508 n e f r o l o g i a 2 0 2 2;4 2(5):506–518 combination of obstruction and infection in the upper urinary (RCTs and q-RCTs), regardless of their publication status or tract.11 language of publication. Moreover, there is also a relationship between hypercal- ciuria and osteopenia and osteoporosis.12–15 Up to 22% of Types of participants children with IH have osteopenia,16 the long-term serious- Studies performed on adults or children with IH, defined as ness of which has yet to be determined even though many calcium excretion greater than 4 mg/kg/day, 250 mg/day in children with osteopenia normalized their bone mineral den- women or 300 mg/day in men (in the absence of any evidence sity without any pharmacological treatment17 . In relation to of secondary cause) undergoing pharmacological treatment to the therapeutic options for the treatment of IH and its comor- control the illness and its complications were included. We bidities, numerous pharmacological treatments can decrease excluded studies that enrolled patients with secondary hyper- levels of calciuria or the urinary crystallization index. How- calciuria or patients suffering other illnesses that could cause ever, the efficacy of these treatments in controlling the illness osteopenia or urinary stones. and preventing the clinical manifestations of IH remains con- troversial. Several meta-analyses have evaluated the effect of Types of interventions medications on preventing kidney stones,18 although very few We investigated the effects of any pharmacological interven- have focused on patients with proven hypercalciuria. tion (longer than 4 months) for preventing complications in IH Thiazides increase calcium reabsorption in the dis- versus a control/comparator (placebo, other pharmacological tal tubule and have demonstrated efficacy in preventing intervention or a different administration mode or dose of the recurrent calcium nephrolithiasis; however, they can also same treatment). We assessed only those interventions with cause glucose intolerance, dyslipidaemia, hyperuricaemia and a follow-up period of at least six months. hypokalaemia, which in turn leads to intracellular metabolic acidosis and hypocitraturia.19 Thiazides may improve bone Types of outcome measures mass density (BMD) in patients with recurrent stones and The primary outcomes of the review were stone-free patients, hypercalciuria, although the long-term effect of their use is urinary symptoms and severe adverse events. The secondary still not very clear.20–22 Indapamide, a non-thiazide diuretic, outcomes included the stone formation rate, changes in BMD, seems to have similar effects and safety profiles.23 quality of life, calciuria and any adverse events. We include a Other drugs, such as citrate salts, orthophosphates or bis- ‘summary of findings’ table reporting the primary outcomes phosphonates, have also shown some beneficial effects, but and stone formation rate using GRADEpro.41 they are not free of potential side effects.24,25 There are several recent studies and reviews on the preven- Data collection and analysis tion of recurrent kidney stones,26–37 but these studies do not analyze the effects of pharmacological interventions in the Four review authors working in pairs assessed all studies using subgroup of individuals with IH. In 2009, our group published a data extraction form and followed the domain-based risk a systematic review about the pharmacological treatment of of bias evaluation as described in the Cochrane Handbook IH,38,39 and our present aim is to update that previous review for Systematic Reviews of Interventions.40 We attempted to while shifting the focus to patient-important outcomes asso- obtain numbers of events and totals for the population for ciated with IH, such as stone formation, severe adverse events dichotomous outcomes and means with standard deviations and urinary symptoms. or data necessary to calculate these statistics for continuous The objective of this systematic review was to assess how outcomes. Unless there was good evidence for homoge- pharmacological interventions can influence several relevant neous effects across studies, we summarized the data using outcomes in patients with IH. a random-effects model. We interpreted the random-effects meta-analyses with due consideration of the whole distribu- tion of effects. We assessed heterogeneity statistically with Materials and methods the I2 value; I2 > 50% indicated substantial heterogeneity.42 We planned to test for asymmetry using the funnel plot, but the Search strategy and selection criteria number of trials was insufficient for comparison. We used Review Manager 5 software (Cochrane Collaboration, Copen- In October 2019, we performed a comprehensive search of hagen, Denmark) to perform the statistical analyses. When the Cochrane Central Register of Controlled Trials, MEDLINE possible, we explored the effect of bias in the effect estimates (Ovid), and Embase databases; clinical trials registries; and and performed predefined subgroup analysis. the grey literature. To identify any studies that may have been missed during the literature search, we checked the reference lists of eligible studies and contacted the authors of identi- Results fied studies for knowledge of any published or unpublished studies, including new studies, additional studies, or works Fig. 1 shows the study flow diagram. Detailed descriptions of in progress. Two review authors independently screened all the included and excluded studies are shown in Table 1 and potentially relevant records and classified studies in accor- Additional file 1, respectively. dance with the criteria for each provided in the Cochrane Included studies are summarized in Table 1. Based on Handbook for Systematic Reviews of Interventions.40 We the results of the new searches, we included a new study, included randomized and quasi-randomized controlled trials which was conducted by Giusti et al.43 Among the five studies n e f r o l o g i a 2 0 2 2;4 2(5):506–518 509 Fig. 1 – Flow diagram of the literature search. included in the previous version of the systematic review, we The results from the risk of bias assessments are summa- included four of them (studies conducted by Ala-Opas et al.,44 rized in Fig. 2, and detailed judgement of each study can be Borghi et al.,45 Fernández-Rodríguez et al.,46 and Ohkawa found in Additional file 1. Most studies had poor reporting of et al.47 ) in the current analysis, whereas the fifth (conducted their characteristics with an unclear risk of bias in multiple by Breslau et al.48 ) was deemed ineligible after reassessment domains. All outcomes were judged to have a high risk of bias, because of the short treatment and follow-up period. All mostly due to a lack of participant and personnel blinding. five included studies were randomized controlled trials set in ambulatory care or academic facilities, with sample sizes that ranged from 32 to 210 patients. The studies included a total of 586 randomized patients, of which 446 had IH and Effect of the intervention, Comparison 1: were analyzed in this review. Four of the studies44–47 included diuretics versus standard control of the disease patients with urinary stones, and one study43 included post- or specific dietary recommendations menopausal patients in which hypercalciuria was detected in the context of a BMD evaluation. All studies included the Four of the five included studies assessed the effect of the addi- assessment of diuretics in one of the treatment arms. One tion of diuretics to the standard control of the disease (periodic study43 compared the use of diuretics with alendronate (a clinical follow-up and general recommendation for increasing medication used for the treatment of BMD disorders). The out- water intake)45–47 or specific dietary recommendations.44 The comes were assessed at the end of the intervention in four results of this comparison are presented by outcome. None of studies43,45–47 ), while in the fifth,44 a longer period of follow-up the studies addressed urinary symptoms, changes in BMD or was established. quality of life. The main outcomes are summarized in Table 2. 510 n e f r o l o g i a 2 0 2 2;4 2(5):506–518 Table 1 – Baseline characteristics and description of the interventions in the included studies. Description of Trial period Country Intervention(s) and Duration of Outcomes patients comparator(s) intervention and follow-up Ala-Opas 198742 IH patients with – Finland I1: hydrochloroth- 24 months for Stone formation: recurrent stones iazide [oral, twice the comparator assessed as stone (n = 32) (age range: per day, and 5 formation rate 28–70 years) 100 mg/day] + bran months/year for (stone/year/patient) [oral, 40 g/day] the intervention and stone-free C1: bran [oral, patients (%). 40 g/day] Calciuria: 24-h urinary excretion * All participants of calcium (as well received also as of magnesium, low-calcium, sodium and low-oxalate and oxalate) was high fluid assessed at 0, 1, 6, (>2.5 L/day) diet 12 and 24 months. recommendations Borghi 199343 IH patients with 1987–1990 Italy I1: indapamide 3 years Stone formation: recurrent stones (at [oral, 2.5 mg/day] assessed as stone least 1 episode I2: indapamide formation rate during the last 3 [oral, (stone/year/patient), years) (n = 75) 2.5 mg/day] + allopurinol stone-free patients [oral, 300 mg/day] (%) and percentage C1: controlled diet of new stones formed during the 3 years of treatment vs. the number of stones formed during the 3 years before treatment (%). Severe adverse events: hypotension and severe hypokalaemia. Calciuria: 24-h urinary excretion of calcium was assessed at 0, 6, 12, 24 and 36 months. Fernández- IH patients with – Spain I1: hydrochloroth- 3 years Stone formation: Rodríguez recurrent stones iazide [oral, assessed as 200644 (more than 1 episode 50 mg/day] stone-free patients during the last 3 I2: hydrochloroth- (%). years) (n = 52) (age iazide [oral, Calciuria: assessed range: 18–65 years) 50 mg/day] + potassium as patients with citrate [oral, 20 hypercalciuria in a mEq/day] dichotomised way. C1: no specific therapy Giusti 200941 Post-menopausal 2003–2006 Italy I1: indapamide 1 year Severe adverse women with IH and (2.5 mg/d) events. low BMD (n = 77) (age C1: alendronate Changes in bone range: 52–79 years) (70 mg/7d) mass density: assessed as BMD at * All participants lumbar spine (LS), received also Ca femoral neck (FN) supplement to or total hip (TH). reach 1000 mg/day Calciuria: assessed and high fluid as 24-h urinary intake advice excretion of (>2 L/day) calcium. n e f r o l o g i a 2 0 2 2;4 2(5):506–518 511 – Table 1 (Continued) Description of Trial period Country Intervention(s) and Duration of Outcomes patients comparator(s) intervention and follow-up Ohkawa 199245 IH patients with 1984–1990 Japan I1: 6 months-5.7 Stone formation: stones (includes Trichlormethiazide years (mean 2.21 assessed as stone some first episode (4 mg/d) + dietary years and 2.14 formation rate stone formers) and fluid advise years for I1 and (stone/year/patient), (n = 210) (age range: C1: dietary and fluid C1, respectively) stone-free patients 16–77 years) advise (%), remission rate and total number of newly formed stones. Severe adverse events: hypercalcaemia, hyperuricaemia, hypokalaemia, hypermagnesemia, hyperchloremia, increased creatinine, clinical adverse events. Calciuria: assessed as 24-h urinary excretion of calcium. Any adverse event. Stone-free patients RR 5.00, 95% CI 0.60–41.88). Assuming that the baseline prob- ability of severe adverse events is 0.1%, the administration of This outcome was reported in all four studies with a total of diuretics would result in 4 more cases per 1000 patients treated 285 patients. (95% CI 0 fewer to 39 more). The QoE was very low, and it was Diuretics likely increased the proportion of stone-free downgraded due to the following study limitations: a high risk patients (Fig. 3a: RR 1.61, 95% CI 1.33–1.96). Assuming that the of performance and detection bias, an unclear risk of selection baseline probability of being stone-free is 45% (based on the bias, a high risk of other biases, and imprecision (few events, observed average risk in the control groups of the analyzed wide confidence interval). studies), the administration of diuretics would result in 274 more stone-free individuals per 1000 patients treated (95% CI Stone formation rate (secondary outcome) 148–432). Among patients treated with diuretics, 103 out of 136 (75.7%) were stone-free at the end of the follow-up, com- Three out of the four abovementioned studies (247 patients) pared with 67 out of 149 (44.9%) in the control group. Although reported stone formation rates.44,45,47 Diuretic treatment the follow-up periods were not homogeneous, particularly in likely reduced the number of stones/patient/year (Fig. 3c: the study conducted by Ohkawa et al.,47 there was no sta- mean difference −0.18, 95% CI −0.30 to −0.06). Therefore, con- tistically significant heterogeneity (I2 = 0%). The QoE for this sidering an average stone formation rate of 60–210 stones/year outcome was moderate due to the following study limitations: in 1000 patients treated, the use of diuretics may cause the a high risk of performance and detection bias, an unclear risk formation of 180 fewer stones/year (60–300 fewer stones/year). of selection bias and a high risk of other biases. The QoE was low, and it was downgraded due to the follow- ing study limitations: a high risk of performance and detection Severe adverse events bias, an unclear risk of selection bias a high risk of other biases, and imprecision (wide confidence intervals that contained val- Borgi et al.,45 reported serious adverse events in two out of 25 ues above and below the thresholds for clinically meaningful patients treated with indapamide: one hypokalaemia event effects). with serum potassium 2.6 mEq/L and one severe hypotension event. In the study conducted by Ohkawa et al.,47 two out of 105 patients treated with thiazides had to stop treatment Calciuria (secondary outcome) because of adverse events compared to no patients in the con- trol group. In the studies conducted by Ala-Opas et al.,44 and Fernandez-Rodriguez et al.,46 did not report calciuria but Fernandez-Rodriguez et al.,46 there were no withdrawals due reported the number of patients with persistent hypercalci- to adverse events, and no further information was provided uria. At the 36-month follow-up, 15 of the 17 patients in the regarding this outcome. control group had persistent hypercalciuria, whereas 8 of the Overall, the use of diuretics may not cause severe adverse 21 patients who received diuretics had persistent hypercalci- events when compared to placebo or no intervention (Fig. 3b: uria (RR 0.43, 95% CI 0.24–0.77). 512 n e f r o l o g i a 2 0 2 2;4 2(5):506–518 Fig. 2 – Risk of bias judgements per domain and study. Green points: low risk bias; Yellow points: unclear risk of bias; Red points: high risk of bias. Ohkawa et al.,47 reported that calciuria decreased to and imprecision (few patients in each group, wide confidence 0.567 mmol/mol creatinine in the thiazide group and to interval for the estimates). 0.641 mmol/mol in the control group at the one-month follow- up (no statistical testing between the groups was performed). Urinary calcium values were available in less than half of the patients at the six-month follow-up. Any adverse events (secondary outcome) Borghi et al.,45 reported that calciuria decreased to 201 mg/24 h (SD 81) in the thiazide group and 330 mg/24 h (SD In two of the studies, adverse events were not clearly 97) in the control group at 36 months of follow-up (mean dif- reported. Ala-Opas et al.,44 stated that adverse events ference of −129.00, 95% CI −184.21 to −73.79). were “uncommon” in the thiazide+bran therapy group, and Ala-Opas et al.,44 reported that calciuria at the 24-month Fernández-Rodríguez et al.,46 provided no data on adverse follow-up was 0.34 mmol/mol creatinine (SD 0.05) in the effects. control group (bran only) and 0.30 mmol/mol creatinine (SD In the study conducted by Ohkawa et al.,47 clinical adverse 0.12) in the thiazide plus bran group (mean difference of reactions, probably due to trichlormethiazide, were observed −0.04 mmol/mol creatinine 95% CI −0.11 to 0.03). in nine patients (8.5%) in the thiazide group: dizziness in Using the random effects model for the meta-analysis, the six, weakness in two and general malaise in one. Only three results of these studies yielded a standardized mean differ- patients (3.7%) in the intervention group showed mild hyper- ence (SMD) of −0.93 (95% CI −1.87 to 0.02; participants = 72; uricaemia (0.50–0.51 mmol/L) in an isolated check-up (versus studies = 2; I2 = 72%). no patients in the control group). Eight patients in the thi- The QoE for this outcome was very low due to an unclear azide group (5.3%) presented with temporary hypokalaemia or high risk of bias in most domains as well as inconsistency (2.8–3.4 mmol/L) compared with no patients in the control group. n e f r o l o g i a 2 0 2 2;4 2(5):506–518 513 Fig. 3 – Comparison 1, diuretics versus control effects on (a) stone-free patients; (b) severe adverse events and (c) stone formation rate (stones/patient/year). 514 n e f r o l o g i a 2 0 2 2;4 2(5):506–518 Table 2 – Summary of findings table for the comparison of diuretics versus control. Population: IH patients with recurrent stones. Settings: Four studies were included in this comparison; 3 were monocentric and performed in Italy, Finland, and Spain; the fourth was a multicentre study performed in 14 centres in Japan. Intervention: Diuretics (including thiazides and indapamide) Control: Standard management (periodic clinical follow-up and general recommendation for increased water intake) Outcomes No. of patients Quality of the Relative effect Anticipated absolute effectsa (95% CI) (studies), follow evidence (95% CI) up (GRADE) Risk with control Risk difference with Diuretics Stone-free 285 (4 RCTs) ⊕⊕⊕ − moderateb RR 1.61 (1.33–1.96) patients Stones follow up: 5–36 450 per 1000 274 more per 1000 assessed by months (148 more to 432 radiography, more) ultrasonogra- phy, pyelography or spontaneous passage Urinary NR (not reported) – – – – symptoms Severe adverse 260 (2 RCTs) − ⊕ − − very lowc,d RR 5.00 (0.60–41.88) events follow up: 6–68 1 per 1000 4 more per 1000 (0 Clinical and months fewer to 39 more) laboratory data Stone formation 247 (3 RCTs) − ⊕⊕ − lowb,e MD −0.18 The mean number 180 fewer rate follow up: 5–68 (−0.30 to −0.06) of stones per 1000 stones/year per 1000 months (stones/patient/year) patients ranged patients (300 fewer Passage, from 60 to to 60 fewer) removal or 210 stones/year. radiographic visualization a The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). IH: Idiopathic hypercalciuria; CI: Confidence interval; RR: Risk ratio; OR: Odds ratio. GRADE framework to evaluate the quality of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. b Downgraded by one level due to study limitations: a high risk of performance and detection bias, an unclear risk of selection bias and a high risk of other biases. c Downgraded by two levels due to severe imprecision: few events resulted in a wide confidence interval. d Downgraded by one level due to study limitations: a high risk of performance and detection bias, an unclear risk of bias in most remaining domains. e Downgraded by one level due to imprecision: very few events resulted in a wide confidence interval. The QoE for this outcome was very low due to the high risk of performance and detection bias, the unclear risk in most Effect of the interventions, Comparison 2: other domains and imprecision (few events in each group). thiazide versus alendronate Only one of the included studies43 assessed the effect of inda- pamide compared to alendronate. This study did not assess Sensitivity analyses the effect of the intervention on stone formation, urinary symptoms, quality of life or non-severe adverse events. The The outcomes evaluated in this meta-analysis showed no main outcomes are summarized in Table 3. statistical heterogeneity; therefore, we did not perform a sensitivity analysis to identify studies contributing to het- erogeneity. Additionally, since heterogeneity was low, the Severe adverse events estimates and confidence intervals were almost identical using fixed effects and random effects models. We could not Indapamide likely does not increase severe adverse events perform a sensitivity analysis according to risk of bias since compared to alendronate (RR 1.69, 95% CI 0.31–9.26). The all study outcomes had a high risk of bias. adverse events associated with alendronate treatment were n e f r o l o g i a 2 0 2 2;4 2(5):506–518 515 Table 3 – Summary of findings for the comparison of diuretics versus alendronate. Population: post-menopausal women with IH and low BMD Settings: one multicentric study performed in 2 centres in Italy. Intervention: diuretics (indapamide) Control: Alendronate Outcomes No. of patients Quality of the Relative effect (95% Anticipated absolute effectsa (95% CI) (studies) evidence (GRADE) CI) follow up Risk with Risk difference with alendronate diuretics Stone-free – – – – – Urinary symptoms – – – – – Severe adverse 51 (1 study) − ⊕⊕ − very lowb,c RR 1.69 (0.31–9.26) events Follow-up: 6–68 74 per 1000 51 more per 1000 (51 Clinical and months fewer to 612 more) laboratory data Stone formation rate – – – – – - not reported a The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). IH: idiopathic hypercalciuria; CI: confidence interval; RR: risk ratio; OR: odds ratio. GRADE framework to evaluate the quality of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. b Downgraded by one level due to study limitations: a high risk of outcome assessment bias and an unclear risk of selection, attrition and other biases. c Downgraded by two levels due to serious imprecision. gastrointestinal symptoms, and those associated with inda- (P < 0.001). The combination of indapamide and alendronate pamide were severe hypotension. Assuming a 7.4% baseline may cause a greater reduction in calciuria compared with probability of severe adverse events, the administration of alendronate or indapamide alone (reduction in 24-h calciuria diuretics would result in 51 more cases per 1000 patients levels up to 49.7 ± 21%, P = 0.012 versus indapamide alone and treated (95% CI 51 fewer to 612 more). P < 0.001 versus alendronate alone). The QoE for this outcome was low due to study limitations The QoE for this outcome was low due to an unclear risk (a high risk of outcome assessment bias and an unclear risk of bias in most domains and imprecision (small sample size, of selection, attrition and other biases) and imprecision. wide confidence intervals). Changes in BMD (secondary outcome) Discussion Indapamide may not increase BMD (an increase of approx- We identified five RCTs that included a total of 446 hypercal- imately 1.0 ± 3.1% in the lumbar spine and a reduction of ciuric adult patients. We did not find studies in children. approximately 0.3 ± 3.5% and 0.4 ± 3.1% in femoral neck and The stone-free patient outcome was analyzed in four stud- total hip, respectively, were observed). In contrast, alendronate ies that included 285 patients and compared the effect of was able to induce an increase in BMD of approximately diuretics with standard control of the disease.43–47 The mod- 5.8 ± 4.2%, 3.9 ± 7.9% and 2.0 ± 3.6% in the lumbar spine, erate to low QoE for these studies indicates that diuretics femoral neck and total hip, respectively. Patients treated with probably increase the number of stone-free patients and may the combination of alendronate plus indapamide showed a reduce the stone formation rate when compared with con- greater increase in lumbar BMD compared with that observed trols. in patients treated with alendronate alone: 8.2 ± 5.3% and We are uncertain whether the use of diuretics is associated 5.8 ± 4.2%, respectively (P < 0.05). with a greater incidence of severe adverse events, but among The QoE for this outcome was low due to an unclear risk the 154 patients treated with diuretics, seven (4.5%) patients of bias in most domains and imprecision (small sample size, had to discontinue the treatment because of adverse events: wide confidence intervals). four due to hypotension, two due to dizziness and general malaise and one due to severe hypokalaemia. None of these Calciuria (secondary outcome) studies reported the effects of these interventions on urinary symptoms. Regarding 24-h calciuria values, Giusti et al.,43 showed Overall, the QoE for studies of specific diuretic treatments decreased values after treatment compared with baseline in is limited due to the use of different types of diuretics, vari- all groups, with reductions of 24.3 ± 19.7% in the alendronate able doses, different follow-up periods, and variable imaging group and reductions of 34.7 ± 18.2% in the indapamide group protocols. 516 n e f r o l o g i a 2 0 2 2;4 2(5):506–518 The comparison of alendronate versus indapamide was 95% CI 1.36–4.05) and new stone formation rate (7 studies, 324 addressed by one study with 77 participants.43 This study did patients: RR 0.26, 95% CI 0.10–0.68) compared to the control not report the number of stone-free patients, urinary symp- condition. We could not draw conclusions about the benefi- toms or stone formation rate. We are uncertain whether the cial effect of citrate in patients with hypercalciuria since we use of diuretics is associated with a greater incidence of severe were not able to obtain separate data on patients with this adverse events when compared with alendronate. underlying metabolic condition. Reports based on small samples of patients suggested The risks associated with pharmacological treatment for benefits of etidronate plus calcium supplementation49 or kidney stones have been reviewed by York et al.,54 and all thiazide20,21 treatments for BMD in patients with hypercalci- possible adverse events were described. Only hypokalaemia, uria. Only Giusti 2009 assessed this outcome in hypercalciuric hypotension and increases in plasma uric acid were reported women with low BMD treated with indapamide and alen- in the included studies in the current meta-analysis. The inci- dronate. The results after one year of treatment showed that dence of adverse events reported by Moe55 was much higher indapamide had a negative effect on BMD compared with (up to 30%) than that reported in the included studies in our alendronate. systematic review (from 2% to 21%). As part of the secondary outcomes, we analyzed the effects of pharmacological interventions on calciuria. Both diuretics and bisphosphonates showed an association with reduced cal- Conclusion ciuria, but we found some inconsistency across comparisons. In general, improvements were observed in the short term, In adult patients with IH and recurrent stones, the addition but evidence for longer periods of control is insufficient. Two of diuretics to a normal or modified diet probably increases studies showed a considerable effect maintained for at least 36 the number of stone-free patients and may reduce the rate months.45,46 However, these studies measured calciuria differ- of stone formation. It is uncertain whether diuretics increase ently (one of them only dichotomously); therefore, the results the occurrence of severe adverse events. There were no stud- should be interpreted with caution. Furthermore, calciuria is ies investigating the effect of pharmacological treatment on only one of the factors associated with stone formation and urinary symptoms in idiopathic hypercalciuria. We found urinary symptom incidence; therefore, its reduction might not no studies performed in children. We suggest that better directly impact clinical outcomes.50 designed, adequately powered clinical trials are required in Although we conducted extensive and sensitive literature patients with idiopathic hypercalciuria to determine with searches without language restriction, the possibility of pub- greater certainty the effects of pharmacological interventions lication bias remains. As four authors screened titles and on these patients compared to diet interventions. abstracts of each record and extracted data independently, we assume that the risk of bias on the review process was low. We attempted to improve the number of studies included by Conflicts of interest contacting four authors for specific data for the hypercalciuric patients, but we were unsuccessful. The authors declare that they have no conflicts of interest. Several systematic reviews and guidelines have sug- gested that diuretics could act as a prophylactic treatment for patients with recurrent urolithiasis and a high risk of Acknowledgements recurrence.36,51,52 Accordingly, our review showed that diuretic treatment in hypercalciuric patients with urolithiasis probably We thank the Cochrane Renal Group and Cochrane Iberoamer- has beneficial effects; diuretic treatment was associated with icana for their help in performing the search strategies. We an increased stone-free patient rate (RR 1.61, 95% CI 1.33–1.96) thank Camila Escobar Liquitay (Cochrane Argentina Instituto and a low incidence of severe adverse events (7/154 patients). Universitario Hospital Italiano) for assistance with updating To date, there is no evidence on the role of pharmacologi- the searches. cal interventions for preventing nephrolithiasis in individuals with hypercalciuria with no previous history of kidney stones. Appendix A. Supplementary data A Cochrane review on dietary interventions for prevent- ing complications in IH53 reported an increase in stone-free patients (RR 1.30, 95% CI 1.02–1.63) under a normal calcium, Supplementary data associated with this article can be found, low protein and low salt diet versus a low calcium diet. 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