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. 2021 Apr 19;16(4):e0250257. doi: 10.1371/journal.pone.0250257

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: A meta-analysis and systematic review

Zhenghao Wang 1, Yu Zhang 1, Wuran Wei 1,*
Editor: Tzevat Tefik2
PMCID: PMC8055022  PMID: 33872340

Abstract

To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) for investigating the effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition. PubMed, Web of Science, Embase, EBSCO, and Cochrane Library databases (updated November 2020) were searched for studies with the following keywords: diet, fluid, recurrent, prevention, randomized controlled trials, and nephrolithiasis. The search strategy and study selection process was conducted by following the PRISMA statement. Six RCTs were identified for satisfying the inclusion criteria and enrolled in this meta-analysis. Our result showed that low protein with or without high fiber diet intervention does not decrease the recurrence of stone upon comparing with control groups (RR = 2.32, 95% CI = 0.42–12.85; P = 0.34) with significant heterogeneity among the studies (I2 = 81%, P = 0.02). But normal-calcium, low protein, low-salt diet had recurrences did reduced the recurrence compared to normal-calcium diet. And the fluid intake has a positive effect on prevention of recurrent stone formation (RR = 0.39, 95% CI = 0.19–0.80; P = 0.01) with insignificant heterogeneity among the studies (I2 = 9%, P = 0.30). The different components of urine at baseline were reported in four studies. Upon reviewing the low protein with or without high fiber dietary therapy groups, it was found that there were no obvious changes in the 24-hour urine sodium, calcium, citrate, urea, and sulfate. In conclusion, our study shows that the only low protein with or without fiber does not affect recurrence, but low Na, normal Ca diet has a marked effect on reducing recurrence of calcium stone. And fluid intake shows a significant reduction in the recurrence of calcium stone.

Introduction

Nephrolithiasis or urolithiasis is the third most common disease of the urinary tract that becomes more prevalent over the past decades [1, 2]. The worldwide kidney stone prevalence rate is 1.7% to 8.8% costs about $2.1 billion in 2020 [3, 4]. Patients with nephrolithiasis often suffer from short-term complications such as acute renal colic, nausea, vomiting, and hematuria, and long-term complications such as chronic renal failure and hydronephrosis [5]. Furthermore, it is often associated with an incidence of recurrence after an initial event of 30% to 50% without prevention [6]. Therefore, to minimize the morbidity of nephrolithiasis, the reduction in calculi recurrence after the surgical clearance of stones is crucial.

The stones are mainly composed of 4 types of components—calcium oxalate, uric acid, calcium phosphate, and struvite, with calcium stones being the most common type [7]. The present study shows that the mechanism of stone formation is mainly based on metabolic defects which are combined from both genetic and nutritional factors [8]. Present efforts to prevent the recurrence of stones are mainly focus on changing the eurine compositions and decreasing concentrations of the lithogenic factors [9]. Currently, medication has a therapeutic effect on the prevention of recurrent stone formation by increasing renal calcium reabsorption, decreasing gut calcium absorption, chelating calcium in the urine or poisoning calcium crystal surfaces. Nevertheless, there are some associated side effects including gastrointestinal reaction, changes in blood pressure, and fluid/electrolyte imbalance [10]. Thus, some life-related prevention has been applied due to its high compliance and low side effects benefits [11]. To reduce calcium stone recurrence, preventive strategies targeting modifiable diet structure may be effective.

Previous studies have shown that formation of a renal stone is closely related to dietary regimes [12, 13]. Nevertheless, the higher evidence-based study like systematic review of clinical value in dietary therapy in urinary stone recurrence is still lacked. Furthermore, new studies with more detailed data at high evidence level are reported. Thus, we performed this systematic review and meta-analysis of randomized controlled trials (RCTs) for investigating the effects of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition.

Materials and methods

This systematic review and meta-analysis followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement and the Cochrane Handbook for Systematic Reviews of Interventions [14]. Ethical approval and patient consent were not required as all the analyses were based on previously published studies.

Literature search and selection criteria

We systematically searched several databases including PubMed, Embase, Web of Science, EBSCO, and the Cochrane Library from the inception until November 2020 with the following keywords: diet, fluid, recurrent, prevention, randomized controlled trials, and nephrolithiasis. The reference list of retrieved studies and relevant reviews were hand-searched, and the process mentioned above was repeatedly performed for ensuring that all eligible studies were included. Inclusion criteria were as follows: (1) RCTs study design, (2) The patient had a stone history and was diagnosed by surgical removal, stone passage, or by imaging systems, (3) the intervention was diet or water intake, (4) adequate reporting of data provided for analysis, and (5) availability of the full text. All languages were included.

Data extraction and outcome measures

Baseline information extracted from the original studies includes the first author, published year, number of patients, patient age and gender distributions, type of calcium stone, and detailed methods for the two groups, and the evaluation of evidence level. Data were independently extracted by two investigators and the discrepancies were resolved by consensus. The primary outcomes were stone recurrence and withdrawal rate. The secondary outcomes were the variables of urine composition.

Quality assessment of individual studies

All assessments were performed independently by two researchers with the differences resolved by the third researcher. the domain-based evaluation recommended by the Cochrane Handbook for Systematic Reviews of Intervention were used to address the following domains: bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported result [15]. Figure of ‘Risk of Bias’ assessment were made by using Review Manager Software Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Statistical analysis

Risk ratio (RR) with 95% confidence intervals (CIs) was calculated for dichotomous outcomes and heterogeneity was evaluated using the I2 statistic, with I2 > 50% indicating significant heterogeneity [16]. Sensitivity analysis was performed for evaluating the influence of a single study on the overall estimate by omitting one study or by performing subgroup analysis. The random-effects model was used for meta-analysis. Owing to the limited number of included studies (<10), publication bias was not assessed. Statistical significance was accepted at P < 0.05. All statistical analyses were performed using Review Manager Software Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results

Literature search, study characteristics, and quality assessment

A total of 71 articles were initially identified from the database search. After the removal of duplicates, 45 articles were retained. Of these, 34 were excluded from analysis following the screening of the abstracts and titles, three were excluded as they were review articles, one was excluded because of insufficient data, and one was excluded because of the unavailability of the full text. Finally, six RCTs were identified as those satisfying the inclusion criteria and were finally enrolled in this meta-analysis [17–22]. The article selection process was performed by following the PRISMA guidelines (Fig 1). Baseline characteristics of the six included RCTs are shown in Table 1. These studies were published between 1996 and 2008, and the total sample size was 824.

Fig 1. Flow diagram of study searching and selection process.

Fig 1

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Table 1. Characteristics of included studies.

No. Author year Experimental group Control group Follow up time(year)
Number (n) Age (Mean±SD) Male (n) Type of stone Method Number (n) Age (Mean±SD) Male (n) Stone type Method
1 Dussol 2008 115 44±12 60 Calcium oxalate 55 patients receive low doses protein (<15% of total energy) and 65 patients receive high doses fiber(>25g) per day 63 45±11 38 Calcium oxalate Normal diet 4
2 Sarica 2006 12 - - Calcium oxalate Enforced fluid intake (achieve to more than 2.5 liters of urine per day) 9 - - Calcium oxalate Nomal diet 3
3 Borghi 2002 60 44.8±9.2 60 Calcium oxalate/ Calcium phosphate Normal Ca with reduced protein 52g/d and salt 50 mmol/d 60 45.4±10.9 60 Calcium oxalate Traditional low Ca diet 5
4 Kocvara 1999 113 18–72 59 Calcium stone Special dietary regimens with low proteins, purine, oxalate and high fiber. 94 18–72 37 Calcium stone Normal diet 3
5 Hiatt 1996 50 43.1±1.5 36 Calcium oxalate 56–64 g/d protein, 75 mg/d purine, fiber supplement and 6–8 glasses of water 49 42.9 ± 1.4 42 Calcium oxalate Fluid intake 4.5
6 Borghi 1996 99 42.2±11.6 70 Calcium oxalate Enforced fluid intake (achieve to more than 2 liters of urine per day) 100 40.4± 13.2 60 Calcium stone Normal diet 5
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Interventions of four studies take the dietary method [17, 19–21]. The study by Dussol et al. has two subgroups: low animal protein and high fiber. Patients in the study by Borghi et al. received a low protein and low salt diet [19]. Kocvara et al. take a special regime based on a metabolic evaluation which involves low protein, purine, oxalate, and high fiber [20]. Hiatt et al. compared the low protein and purine with fluid intake only [21]. The other two studies take water intake to make the urine volume higher than 2 L and 2.5 L, respectively [18, 22].

Quality assessment of included studies

All studies had low risk bias in incomplete outcome data, selective reporting and other issues. Three studies [18, 20, 22] had high risk in blindness and random sequence generation while the other three studies [17, 19, 21] were not which is shown Fig 2.

Fig 2. Risk of bias assessment in included studies.

Fig 2

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Primary outcome: Recurrence rate and withdrawal rate

Totally Four studies reported the recurrence of the stones by the dietary method [17, 19–21] and two by the fluid method [18, 22]. Due to interventions for control group of Kocvara et al. [20] are tailored. Therefore, their result of recurrence rate cannot compare with Hiatt et al. and Dussol et al. And Borghi et al reported normal-calcium, low protein, low-salt diet had recurrences did reduced the recurrence compared to normal-calcium diet (12/60 vs 20/60; RR = 0.49, 95%CI = 0.24–0.98) [19]. And, only two studies [17, 21] were included to evaluate the effect of only trials of low protein with or without high fiber diet method. A random-effects model was used for analyzing the primary outcomes. Our result showed that dietary intervention does not decrease the recurrence of stone upon comparing with control groups (RR = 2.32, 95% CI = 0.42–12.85; P = 0.34) with significant heterogeneity among the studies (I2 = 81%, P = 0.02) (Fig 3). However, the fluid intake was found to have a positive effect on the prevention of stone recurrence (RR = 0.39, 95% CI = 0.19–0.80; P = 0.01) with insignificant heterogeneity among the studies (I2 = 9%, P = 0.30, Fig 4).

Fig 3. Forest plot for the meta-analysis of recurrence of only low protein with or without high fiberdiet.

Fig 3

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Fig 4. Forest plot for the meta-analysis of recurrence rate of liquid intake.

Fig 4

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Three dietary groups reported the rate of withdrawal of patients. Though the result is statistically insignificant (RR = 0.76, 95% CI = 0.59–0.98; P = 0.03) insignificant heterogeneity was observed among the studies (I2 = 0%, P = 0.81, Fig 5). All the studies showed that intervention groups have a higher withdrawal rate. All patients in fluid intervention froup finish the follow up.

Fig 5. Forest plot for the meta-analysis of withdraw rate.

Fig 5

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Secondary outcome: Variables of urine composition

The Urinary variables at baseline were reported in four studies [17–20]. The urine volume was reported in all four studies and one fluid intake group were changed significantly. The 24-hour urine sodium, calcium, citrate, urea, and sulfate were reviewed in other dietary therapy groups. Borghi et al. reported urine sodium and oxalate changed in their study as their was a unique one which provided both low protein and low salt [19]. And Kocvara et al. showed that calcium and oxalate changed in their study [20]. Two studies reported the relative oxalate saturation and both their changes are significant [18, 19].

Sensitivity analysis

Among all outcomes, the dietary intervention showed a significant heterogeneity (I2 = 81%, P = 0.02). The heterogeneity may come from the study design as the specific dose of protein are different.

Discussion

Prevention of kidney stone recurrence is very complex and controversial. A cohort study showed that about half of the nephrolithiasis were ascribed to lifestyle factors [11]. Particularly, diet interventions were assumed as an efficient technique to prevent urinary stone formation and its recurrence. However, due to the lack of high-quality original research, no conclusive consensus or guideline was drawn for the effect of secondary prevention for stone formation [23]. Here, we conducted this study to review the RCTs reporting the effects of different dietary interventions for the prevention of recurrent stone formation and the changes in urine compositions in patients with urinary stone disease.

The results of this study indicate that water intake can reduce stone recurrence. Meanwhile low protein with or without fiber does not affect recurrence, but low Na, normal Ca diet has a marked reduction effect on recurrence. All included studies use reduced protein intake for patients as an intervention process. Higher animal protein intake may result in decreased citrate and urine PH and increased urinary excretion of calcium and uric acid which may potentially favor the formation of stones [24]. But the present study unexpectedly contradicted this hypothesis. In one subgroup of the study by Dussol et al., the only intervention is the restriction of the consumption of animal protein, but the recurrence rate was 48% (11 of 23) in the intervention group which is almost the same as that for the control group (48%;11 of 23) [17]. Also, Hiatt et al. reported that dietary intervention combining low protein, high fiber, and fluid intake has no advantage compared to fluid intake only [21]. An alternative explanation is that different types of protein may affect the recurrence of kidney stones differently. One large cohort study showed that red and processed meats increase the risk of stone formation than other animal or vegetable protein [25]. This is difficult to control in long-term RCTs. Furthermore, protein intake causes an increase in excretion of lithogenic materials such as calcium oxalate, sulfate, and uric acid, and causes a reduction in the excretion of citrate [26, 27]. But our study shows that these changes are not obvious (Table 2). Not all stone formation compositions of the urine increase correspondingly and urine citrate decreased statistically insignificant. This may suggest that low-protein intake is not low enough to provide the desired effect. Dussol et al. assumed that their intervention with low animal protein (17% total energy) is not low enough compared to the people who often follow a Mediterranean diet that is relatively poor in animal protein [17]. However, Borghi et al. added low Na with normal Ca in diet reduced the probability of stone recurrence which indicated the positive effect of low Na for prevention the stone [19].

Table 2. Urinary compositions variables in baseline and the long term follow up.

Study Follow up Method Urine volume (L/day) Sodium (mmol/day) Calcium (mmol/day) Oxalate (mmol/day) Citrate (mmol/day) Urea (mmol/day) Sulfate (mmol/day) Relative oxalate saturation
Baseline Result Baseline Result Baseline Result Baseline Result Baseline Result Baseline Result Baseline Result Baseline Result
Dussol 3 year Low protein 1.8±0.6 1.9±0.8 149±44 171±71 6.8±3.1 7.0±3.5 0.30±0.1 0.29±0.1 2.9±1.9 2.9±1.5 381±95 359±135 4.3±1.9 3.1±2.4
High fiber 2.0±0.7 1.8±0.6 163±58 154±55 6.9±3.7 7.0±3.5 0.31±0.2 0.32±0.1 3.3±3.2 2.1±1.2 354±93 361±117 4.6±2.8 4.8±3.6
Borghi 3 year Low protein Low salt 1.9±6.7 2.1±5.2 205±64 127±66b 7.0±3.4 6.6±2.4 0.42±0.1 0.33±0.1b 505±142 447±113 2.8±0.8 2.5±0.6 6.7±4.5 4.5±2.9a
Kocvara 3 year Special diet 2.4±6.5 2.4±6.5 5.1±2.4 6.4±2.8b 0.35±0.2 0.42±0.2a 3.0±1.5 3.2±1.9
Borghi 5 year Fluid intake 1.1±0.2 2.6±0.7b 1.8±1.7 1.2±1.0b
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a: P<0.05 compared to the baseline;

b:P<0.01 compared to the baseline

The definition of “low” for “low protein” is still unclear. Another reason is that each patient’s daily diet structure is complex as a low protein diet may change the urine composition in a very short follow-up period but may not in an interventional long-term trial. Furthermore, specific dietary instructions should be corrected according to repeated metabolic measurements and low protein intake could produce other metabolic disorders [12]. Kocvara et al. found a positive result in their study as each patient underwent a personalized metabolic assessment and specific diet regime. And patients with hypercalciuria and hyperuricemia took a low protein diet can significantly reduce the recurrence of stones [20]. Rotily et al. also found in a 24-hour urine composition analysis that patients with hypercalciuria benefit more from a low protein diet as the urea and calcium outputs were observed only among hypercalciuria patients [28]. Therefore, we can conclude that a low-protein diet does not prevent the recurrence of stones in all patients, but it may benefit patients with hypercalciuria. Thus, metabolic evaluation is strongly recommended for patients before choosing low protein diet therapy. The withdrawal rate in low protein is higher than in the control group. Also, Dussol et al. and Borghi et al. reported that the rate of unwillingness for withdrawal patients to continue the therapy is also higher which indicates poor patient compliance though it is statistically insignificant [17, 19].

Our results show that an increase in dietary fiber intake failed to reduce the recurrence rate of calcium oxalate stones. In the study by Dussol et al., the subgroup taking a high diet only did not succeed in the prevention of recurrence as well as the changes in urine composition [17]. This result is similar to the study by Rotily et al. in which the patients with dietary fiber intake do not reduce the predictive factors of calcium oxalate such as calcium or oxalate outputs [28]. Haitt et al. found that a combination of high fiber and low protein diet did not reduce stone recurrence [21]. Phytate in fibers can reduce hypercalciuria by forming complex molecules with calcium in the gut [29]. Therefore, fiber-rich foods can decrease calcium oxalate supersaturation and increase citrate excretion [30]. Nevertheless, intestinal complexation of calcium might lead to hyperoxaluria [31]. So, the overall effect of high fiber in preventing the recurrence of calcium oxalate stones is unclear. An observational study by Hirvonen et al. showed that a fiber-rich diet may increase the recurrence of kidney stones [32]. Other results of recent cohort studies reported fiber-rich diet might reduced recurrence or no relation for stone formation [33, 34]. The results that fluid intake reduced stone recurrence were not surprising. Increased fluid intake may help prevent the formation of stones by diluting urine components and decreasing urine acidity which is well learned and suggested as the first prevention step for urolithiasis [35]. This concept is consistent with the results of Borghi et al. which showed a significant reduction in the relative supersaturation of calcium oxalate, brushite, and uric acid [18]. It is worth noting that there is no withdrawal patient in two fluid intake groups indicating that water intake is highly associated with patient compliance.

There are a few limitations associated with this study. Firstly, the heterogeneity of dietary prevention is high due to the variation in the intervention standards in the study design. Secondly, the impact of dietary factors on stone recurrence varies from age, gender, race, and region remained unknown due to the lack of related studies. Lastly, the accuracy of our summary may be skewed as there are publication biases due to some unpublished data.

In conclusion, our study shows that the only low protein with or without fiber does not affect recurrence, but low Na, normal Ca diet has a marked effect on reducing recurrence of calcium stone. And fluid intake shows a significant reduction in the recurrence of calcium stone.

Supporting information

S1 Checklist. Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: A meta-analysis and systematic review.

(DOC)

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S1 Table. S1 Table for quality assessment in all the selected studies for systematic review and meta-analysis.

(DOCX)

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S1 Data. All relevant data of this study.

(DOCX)

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S1 Search strategy

(DOCX)

Click here for additional data file. (15.3KB, docx)

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The authors received no specific funds for this work.

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  • 32.Hirvonen T, Pietinen P, Virtanen M, Albanes D, Virtamo J. Nutrient intake and use of beverages and the risk of kidney stones among male smokers. American journal of epidemiology. 1999;150(2):187–94. Epub 1999/07/21. 10.1093/oxfordjournals.aje.a009979 . [DOI] [PubMed] [Google Scholar]
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  • 34.Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. Journal of the American Society of Nephrology: JASN. 2004;15(12):3225–32. Epub 2004/12/08. 10.1097/01.ASN.0000146012.44570.20 . [DOI] [PubMed] [Google Scholar]
  • 35.Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Beverage use and risk for kidney stones in women. Ann Intern Med. 1998;128(7):534–40. Epub 1998/06/10. 10.7326/0003-4819-128-7-199804010-00003 . [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Tzevat Tefik

26 Jan 2021

PONE-D-20-37694

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: a meta-analysis and systematic review

PLOS ONE

Dear Dr. Wei,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

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Tzevat Tefik, MD

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Is the manuscript technically sound, and do the data support the conclusions?

With respect to their ability to adhere to guidelines for performance of meta-analyses, I do not have enough experience to judge. However, they have combined studies that do not test the same interventions, which leads to inappropriate conclusions. The Results section dealing with the ability of diet interventions to prevent stone recurrence is poorly written and confusing, and the figure that illustrates their findings lacks one of the 4 studies being analyzed. The data in the underlying papers partially supports their conclusions; for example the 2 studies of increased fluid do show decreased stone recurrence. The studies of diet alone however are not analyzed appropriately, and thus do not support their conclusions.

Is the manuscript presented in an intelligible fashion and written in standard English?

It could use some editorial polishing to improve the grammar. Also a few typos. The primary results section is hard to follow.

The authors have done a meta-analysis of studies in which dietary interventions were done for nephrolithiasis, with recurrent stone formation as the primary outcome. They found 6 randomized controlled trials of diet or fluid intake that satisfied their criteria. The 2 studies of increased fluid intake appear to be comparable, and both show decreased stone recurrence in the group with increased fluid intake. However the authors conclude that diet interventions did not significantly reduce stone recurrence.

Comments for the investigators:

2. 1. The Introduction includes the statement that “medication has a therapeutic effect on the prevention of recurrent stone formation by reducing the tubular reabsorption or increasing the intestinal reabsorption of calcium.” This is incorrect, and in fact these changes in renal or intestinal calcium handling would actually lead to higher urine calcium excretion. The effect of thiazide is to increase renal calcium reabsorption, in addition to a modest effect to decrease gut calcium absorption. The effect of citrate is multifactorial, and includes its ability to chelate calcium in the urine, and to poison calcium crystal surfaces; it may also lower urine calcium by increasing renal calcium reabsorption.

3. 2. The authors used the Jadad scale to assess for study quality. The 3 items in the scale assess randomization (2 possible points), blinding (2 possible points), and accounting for all patients (1 point). The authors need to justify use of this scale for long-term dietary/fluid studies in which blinding is not attempted or likely to succeed. If possible, a more appropriate scale should be used which was designed for this purpose.

4. 3. The diet studies are not strictly comparable with respect to the interventions carried out. Diet alone is not an intervention, rather the specific type of diet interventions is what is being tested. For background: The 4 diet studies comprise 9 study arms. Three studies have 2 arms, while Dussol has three (control and 2 interventions). The control arms in three studies (Hiatt, Kocvara, and Dussol) are somewhat similar (normal calcium intake, encourage fluids) while the interventions vary. Two of these studies specifically study animal protein and fiber in the diet. In Hiatt, the intervention is low animal protein, increased fruits and vegetables, and bran; in Dussol the 2 intervention arms compare low animal protein (arm 1) with increased fruits and vegetables and whole grain (arm 2). Patient numbers are quite small in Dussol due to drop outs. In Hiatt, the control arm does better with respect to stone recurrence, while in Dussol the three arms all have a very high recurrence rate; both studies follow patients for about 4 years. Overall, it seems fair to say that low animal protein diet, with or without high fiber (or high fiber diet alone), does not prove to lower stone recurrence better than a diet with high fluid and normal calcium intake alone, based on these 2 studies. The recurrence rates per year do vary a lot in these studies, and the authors do not attempt to report them. I suggest that the authors use only these 2 studies to evaluate the effect of protein restriction and fiber.

5. 4. The diet studies by Kocvara and by Borghi are not so readily compared with Hiatt and Dussol. While the control arm of Kocvara is similar, what is being tested in the intervention arm is not a specific diet, but rather the concept that diet prescription based on metabolic workup, rather than generic advice, is beneficial, and the study results bear this out. Thus this study does not really test a specific diet per se, but rather whether diets should be tailored or generic. This study does not really belong in this analysis, as the type of dietary advice is unknown in the intervention group, being individualized to each patient.

6. 5. The diet study by Borghi compares low calcium diet (a unique diet arm which differs markedly from the control arms in other studies) to a diet with low sodium intake (not studied in any of the other studies), along with normal calcium intake, and modestly low animal protein intake. The fact that sodium restriction is the main intervention is clearly shown in Table 2, in which urine Na clearly falls on follow-up, while urine urea does not. The authors should not analyze this study as a low protein trial, because it was sodium restriction which was the major intervention. At 5 years (the study endpoint) the recurrence rates are much lower in the low sodium arm compared to low calcium diet This study is not a simple low protein trial, and should not be included with the 2 explicitly low protein diet trials. In addition, the patient group in this study differs from the other trials, in that idiopathic hypercalciuria, rather than only calcium stone formation, was an explicit study inclusion criteria. The authors should rectify the errors in analysis of this trial, and analyze it as a unique study

7. 6. The paragraph titled Primary Outcome in results describes an analysis which seems to include all the diet studies (ref 17, 20-22) but Figure 2 shows only Dussol, Hiatt, and Kocvar.

Overall, the analysis does not compare like to like, lumping non-comparable studies together, Its handling of the Borghi diet trial is particularly unclear, and therefor the conclusion that dietary intervention does not decrease recurrence of calcium stone does not appear to be valid. A more limited conclusion, that low protein diet, with or without increased fiber, has not proven to lower calcium stone recurrence, may be justified.

Reviewer #2: I believe that this paper is of value because it confirms on the one hand that fluid intake affects stone formation and cast into doubt that urinary risk factors are important in this regard. I suggest that the authors emphasize a few findings in their discussion. Firstly, authors should emphasize that their study investigates as a primary outcome stone RECURRENCE per se as opposed to stone RISK FACTORS. This is important. Second, the findings which refute popular views are equally important, namely that diet does not affect recurrence, that diet does not affect urine composition and that the latter does not affect the former. These are new and provocative findings and will initiate a re-think among stone researchers. Indeed, authors can challenge readers by posing a question about the clinical value of dietary interventions in the first place. Yes, this will be controversial, but that's what differentiates this study from others.

**********

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Reviewer #1: No

Reviewer #2: Yes: Allen Rodgers

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PLoS One. 2021 Apr 19;16(4):e0250257. doi: 10.1371/journal.pone.0250257.r002

Author response to Decision Letter 0

10 Feb 2021

Reviewer #1：

1. The Introduction includes the statement that “medication has a therapeutic effect on the prevention of recurrent stone formation by reducing the tubular reabsorption or increasing the intestinal reabsorption of calcium.” This is incorrect, and in fact these changes in renal or intestinal calcium handling would actually lead to higher urine calcium excretion. The effect of thiazide is to increase renal calcium reabsorption, in addition to a modest effect to decrease gut calcium absorption. The effect of citrate is multifactorial and includes its ability to chelate calcium in the urine, and to poison calcium crystal surfaces; it may also lower urine calcium by increasing renal calcium reabsorption.

Response: We are very sorry for the mistake and appreciated for the reviewer’s correction. We have corrected this part as the comment (Currently, medication has a therapeutic effect on the prevention of recurrent stone formation by increasing renal calcium reabsorption, decreasing gut calcium absorption, chelating calcium in the urine or poisoning calcium crystal surfaces.).

2. The authors used the Jadad scale to assess for study quality. The 3 items in the scale assess randomization (2 possible points), blinding (2 possible points), and accounting for all patients (1 point). The authors need to justify use of this scale for long-term dietary/fluid studies in which blinding is not attempted or likely to succeed. If possible, a more appropriate scale should be used which was designed for this purpose.

Response: Thanks for this professional comments. We have changed the assessment tool. We used the risk bias tool of Cochrane Handbook for Systematic Reviews of Intervention which is more evidence based and we changed this part correspondingly.

3. The diet studies are not strictly comparable with respect to the interventions carried out. Diet alone is not an intervention, rather the specific type of diet interventions is what is being tested. For background: The 4 diet studies comprise 9 study arms. Three studies have 2 arms, while Dussol has three (control and 2 interventions). The control arms in three studies (Hiatt, Kocvara, and Dussol) are somewhat similar (normal calcium intake, encourage fluids) while the interventions vary. Two of these studies specifically study animal protein and fiber in the diet. In Hiatt, the intervention is low animal protein, increased fruits and vegetables, and bran; in Dussol the 2 intervention arms compare low animal protein (arm 1) with increased fruits and vegetables and whole grain (arm 2). Patient numbers are quite small in Dussol due to drop outs. In Hiatt, the control arm does better with respect to stone recurrence, while in Dussol the three arms all have a very high recurrence rate; both studies follow patients for about 4 years. Overall, it seems fair to say that low animal protein diet, with or without high fiber (or high fiber diet alone), does not prove to lower stone recurrence better than a diet with high fluid and normal calcium intake alone, based on these 2 studies. The recurrence rates per year do vary a lot in these studies, and the authors do not attempt to report them. I suggest that the authors use only these 2 studies to evaluate the effect of protein restriction and fiber. The diet studies by Kocvara and by Borghi are not so readily compared with Hiatt and Dussol. While the control arm of Kocvara is similar, what is being tested in the intervention arm is not a specific diet, but rather the concept that diet prescription based on metabolic workup, rather than generic advice, is beneficial, and the study results bear this out. Thus this study does not really test a specific diet per se, but rather whether diets should be tailored or generic. This study does not really belong in this analysis, as the type of dietary advice is unknown in the intervention group, being individualized to each patient.

Response：Thanks for this comment. We have removed the Kocvara et al. for the analysis for recurrent rate and only take Hiatt and Dussol into primary outcome as comment. And the result did not changed as the new result showed that dietary intervention does not decrease the recurrence of stone upon comparing with control groups (RR = 2.32, 95% CI = 0.42–12.85; P = 0.34) with significant heterogeneity among the studies (I2 = 81%, P = 0.02). Meanwhile, we keep Kocvara et al in our study because the data of withdraw rate and changes in the urine compositions. We have corrected this part in our study accordingly.

4. The diet study by Borghi compares low calcium diet (a unique diet arm which differs markedly from the control arms in other studies) to a diet with low sodium intake (not studied in any of the other studies), along with normal calcium intake, and modestly low animal protein intake. The fact that sodium restriction is the main intervention is clearly shown in Table 2, in which urine Na clearly falls on follow-up, while urine urea does not. The authors should not analyze this study as a low protein trial, because it was sodium restriction which was the major intervention. At 5 years (the study endpoint) the recurrence rates are much lower in the low sodium arm compared to low calcium diet This study is not a simple low protein trial, and should not be included with the 2 explicitly low protein diet trials. In addition, the patient group in this study differs from the other trials, in that idiopathic hypercalciuria, rather than only calcium stone formation, was an explicit study inclusion criteria. The authors should rectify the errors in analysis of this trial, and analyze it as a unique study

Response: This is a very good comment. Sorry for ignorance of the effect of a low-salt diet on changes in the composition of urine in Borghi et al. study. And we have added the low salt diet in table two. And we have corrected the result part and described uniqueness of this study.

5. The paragraph titled Primary Outcome in results describes an analysis which seems to include all the diet studies (ref 17, 20-22) but Figure 2 shows only Dussol, Hiatt, and Kocvar.

Response: Sorry for the mistake we made. Though there are four studies reported the diet method, only three study reported the recurrence rate. Actually, Borghi et al. just reported the changes of urinary composition thus only three studies were included into the analysis (ref 16,19,20; Figure 2) and we have corrected this part.

6.Overall, the analysis does not compare like to like, lumping non-comparable studies together, Its handling of the Borghi diet trial is particularly unclear, and therefore the conclusion that dietary intervention does not decrease recurrence of calcium stone does not appear to be valid. A more limited conclusion, that low protein diet, with or without increased fiber, has not proven to lower calcium stone recurrence, may be justified.

Response: Thanks for this important comment. After re-examining our conclusions, we realized that they were too general to be drawn. Therefore, the limited conclusion is needed and we have correct according to this comments.

Reviewer #2:

1.Firstly, authors should emphasize that their study investigates as a primary outcome stone RECURRENCE per se as opposed to stone RISK FACTORS. This is important.

Response: It is a very good comment which may make our study clearer. After careful re-read for our study, we changed the description like “increase the risk of stone” into “increase the recurrence of stone”; “reduced risk or no relation for stone formation” into “reduced recurrence or no relation for stone formation” to emphasize the primary outcome stone recurrence according to comment. Meanwhile, our introduction and conclusion part also emphasize the aim of this study is to “investigating the effects of dietary treatment and fluid intake on the prevention of recurrent calcium stones”.

2.Second, the findings which refute popular views are equally important, namely that diet does not affect recurrence, that diet does not affect urine composition and that the latter does not affect the former. These are new and provocative findings and will initiate a re-think among stone researchers. Indeed, authors can challenge readers by posing a question about the clinical value of dietary interventions in the first place. Yes, this will be controversial, but that's what differentiates this study from others.

Response: Thank you for your appreciation and this very good comment on revision. We reorganized part of introduction and add this sentence “Previous studies have shown that formation of a renal stone is closely related to dietary regimes [12, 13]. Nevertheless, an evidence-based study of clinical value in dietary therapy in urinary stone recurrence is still lacked. Furthermore, new studies with more detailed data at high evidence level are reported.” With this sentence, we pose a question about the clinical value of dietary interventions in the first place and differentiates this study from others as the comments.

Acknowledgment: Our deepest gratitude goes to the reviewers and editors for their careful work and thoughtful suggestions that have helped improve this paper substantially. We also thanks for both their meaningful comments and recognition to our study again.

Attachment

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Decision Letter 1

Tzevat Tefik

9 Mar 2021

PONE-D-20-37694R1

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: a meta-analysis and systematic review

PLOS ONE

Dear Dr. Wei,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 23 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Tzevat Tefik, MD

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have responded to the prior comments, but I have some comments about the current manuscript.

1. In the Introduction, the authors state that “..an evidence-based study of clinical value in dietary therapy in urinary stone recurrence is still lacked”. It is unclear why the authors make this statement, as they are reviewing a number of evidence based studies. What do they feel is lacking?

2. In the section on selection criteria, they specify that the in the studies they selected “patient had stone that has been cleared by surgery”. This is incorrect. The studies they are using do not require surgical removal of stones, only stone passage (or removal) or in some cases visualization on Xray.

3. In the section on Primary outcome, they state that 5 of the studies reported stone recurrence, omitting the Borghi trial of low sodium diet. This is incorrect. That study does report stone recurrence: “Twenty-three of the 60 men on the low-calcium diet and 12 of the 60 on the normal-calcium, low protein,

low-salt diet had recurrences. The cumulative incidence of recurrent stones in the two groups is

shown in Figure 2. The relative risk of a recurrence among the men in the normal-calcium, low-protein,

low-salt group, as compared with the men in the low calcium group, was 0.49 (95 percent confidence interval,

0.24 to 0.98; P=0.04).” This data should be added to the section on primary outcome.

4. The authors continue to refer to “diet method” as the intervention being studied. This is incorrect. The authors need to specify what type of diet is being evaluated. In the case of Hiatt and Dussol, it is low protein with or without high fiber. They should modify the statement in “Primary outcome:recurrence rate” to make clear that this type of diet did not reduce stone recurrence rate.. They should also make clear that the Borghi study of normal calcium, low sodium diet did reduce recurrence rate. They should also modify Figure 3 accordingly, although given that there is only one study of low Na, normal Ca diet it is not clear that Borghi can be added to the plot. However, the legend should make clear that only trials of low protein with or without high fiber are included.

5. The materials do not include Figure legends.

6. The authors state in the Discussion that changes in diet do not affect recurrence. This is incorrect. Low protein diet does not affect recurrence, while low Na, normal Ca diet has a marked effect on recurrence. This statement must be changed.

Reviewer #2: The main interest in this study is that its findings are contrary to popular dogma. As such it is likely to attract a lot of attention

**********

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Reviewer #1: No

Reviewer #2: Yes: Allen Rodgers

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PLoS One. 2021 Apr 19;16(4):e0250257. doi: 10.1371/journal.pone.0250257.r004

Author response to Decision Letter 1

10 Mar 2021

Reviewer #1:

1. In the Introduction, the authors state that “..an evidence-based study of clinical value in dietary therapy in urinary stone recurrence is still lacked”. It is unclear why the authors make this statement, as they are reviewing a number of evidence-based studies. What do they feel is lacking?

Response：This is a very good comment. What we mean is higher evidence-based study like systematic review and meta-analysis and we have changed this part. We have changed the vague expression and thank you for your correction.

2. In the section on selection criteria, they specify that the in the studies they selected “patient had stone that has been cleared by surgery”. This is incorrect. The studies they are using do not require surgical removal of stones, only stone passage (or removal) or in some cases visualization on Xray.

Response：Thanks for comment. We have checked our origin study design and found the mistake in our description. The inclusion criteria is patient had a stone history and was diagnosed by surgical removal, stone passage, or by imaging systems. And we correct this part in our study.

3. In the section on Primary outcome, they state that 5 of the studies reported stone recurrence, omitting the Borghi trial of low sodium diet. This is incorrect. That study does report stone recurrence: “Twenty-three of the 60 men on the low-calcium diet and 12 of the 60 on the normal-calcium, low protein, low-salt diet had recurrences. The cumulative incidence of recurrent stones in the two groups is shown in Figure 2. The relative risk of a recurrence among the men in the normal-calcium, low-protein, low-salt group, as compared with the men in the low calcium group, was 0.49 (95 percent confidence interval, 0.24 to 0.98; P=0.04).” This data should be added to the section on primary outcome.

Response：Thanks for this very good comment. We ignore the result of Borghi trial and made an incomplete conclusion. And we have added the Borghi trail result into the primary outcome. And correcting the our related conclusion for diet intervention into two part：1. Low protein with or without high fiber do not affect the recurrence； 2. normal calcium, low sodium diet did reduce recurrence rate, as comment. Therefore, our conclusions are completer and more accurate.

4. The authors continue to refer to “diet method” as the intervention being studied. This is incorrect. The authors need to specify what type of diet is being evaluated. In the case of Hiatt and Dussol, it is low protein with or without high fiber. They should modify the statement in “Primary outcome: recurrence rate” to make clear that this type of diet did not reduce stone recurrence rate. They should also make clear that the Borghi study of normal calcium, low sodium diet did reduce recurrence rate. They should also modify Figure 3 accordingly, although given that there is only one study of low Na, normal Ca diet it is not clear that Borghi can be added to the plot. However, the legend should make clear that only trials of low protein with or without high fiber are included.

Response：Thanks for this comment. Hiatt and Dussol study show low protein with or without high fiber do not affect the recurrence. And Borghi study shows normal calcium, low sodium diet did reduce recurrence rate. We changed the primary result, figure legend and conclusion accordingly.

5. The authors state in the Discussion that changes in diet do not affect recurrence. This is incorrect. Low protein diet does not affect recurrence, while low Na, normal Ca diet has a marked effect on recurrence. This statement must be changed.

Response：Thanks for this detailed comment. This statement is too general which is incorrect, and we have corrected the statement correspondingly as comment in discussion part (Second paragraph; line 2) and conclusion part.

Acknowledgment: Thanks again. Our deepest gratitude goes to the you for your careful work and detailed comment that have helped improve the quality of our study.

Reviewer #2: The main interest in this study is that its findings are contrary to popular dogma. As such it is likely to attract a lot of attention.

Acknowledgment: Thank you for your recognition of our article. At the same time, we also deeply thank you for your careful and detailed review work. It is your very detailed and professional comments that make our articles more scientific and more complete.

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Decision Letter 2

Tzevat Tefik

5 Apr 2021

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: a meta-analysis and systematic review

PONE-D-20-37694R2

Dear Dr. Wei,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Academic Editor

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Reviewers' comments:

Acceptance letter

Tzevat Tefik

8 Apr 2021

PONE-D-20-37694R2

Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: a meta-analysis and systematic review

Dear Dr. Wei:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Dr. Tzevat Tefik

Academic Editor

PLOS ONE

Associated Data

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    Supplementary Materials

    S1 Checklist. Effect of dietary treatment and fluid intake on the prevention of recurrent calcium stones and changes in urine composition: A meta-analysis and systematic review.

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    S1 Table. S1 Table for quality assessment in all the selected studies for systematic review and meta-analysis.

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