REVIEW Ramadan Fasting and Kidney Stones: A Systematic Review Mohsen Amjadi1, Farzin Soleimanzadeh1*, Hamidreza Ghamatzadeh2, Sakineh Hajebrahimi3, Hossein Hosseinifard4, Hanieh Salehi Pourmehr3, Fateme Tahmasbi2 Purpose: Ramadan fasting in Muslims may contain several hours of abstaining from food and drinking in any kind. This can potentially increase the risk of urinary stone disease. Current literature on possible effects of Ram- adan fasting on urolithiasis is rather limited. Having the gap in scientific background, we decided to evaluate the available comparative information in this systematic review. Materials and Methods: We included all studies comparing fasting and non-fasting conditions, studies evaluat- ing stone formation and clinical manifestations of kidney stone disease. All the English studies published from January 1980 to the end of 2019 were included. The exclusion criteria were as followed: fasting out of Ramadan, non-comparative studies, animal studies, patients with bladder stones, and studies evaluating conditions that are only indirectly related to the stone formation or clinical manifestations of it. Applying the Joanna Briggs Institute (JBI) methodology for systematic review showed the quality of included studies was not high. Results: Only five studies remained after exclusion. Meta-analysis was not applicable due to the diversity in meth- ods and evaluated population. Conclusion: Main trend of the included studies is toward showing no difference between fasting and non-fasting conditions in terms of renal stone formation. However, generalization of the findings to greater populations should be applied carefully considering the heterogeneity of results and quality of studies. Keywords: fasting; kidney calculi; kidney diseases; systematic review INTRODUCTION Ramadan is the ninth month of the Islamic lunar calendar, during which Muslims fast for a whole month. Fasting in Ramadan means abstaining from eat- ing, drinking, and smoking from dawn to dusk. Some conditions, either physiological or pathophysiological, can exempt one from fasting, including pregnancy, breastfeeding, and some disabilities (at their own dis- cretion or the doctor's)(1,2). Muslims eat two meals a day during this month. One meal before dawn, known as Sahar, and the other after sunset, called Iftar.(3) Com- plete restriction of food and fluids intake from sunrise to sunset can lead to different levels of dehydration in fasting people. Due to the low intake of fluids, the body responds to these changes by reducing urine output and increasing urine concentration as an attempt to reach normal ho- meostasis.(4) If proper care is not taken to ensure a hy- drating diet during non-fasting hours, dehydration can be a serious complication and can even lead to death.(5) Due to the increased urine concentration resulting from low fluid intake, changes in the renal system are expect- 1Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. 2Student Research Committee, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. 3Research Center for Evidence Based Medicine, Iranian EBM Centre, A Joanna Briggs Institute Affiliated Center, Tabriz University of Medical Sciences, Tabriz, Iran. 4Department of Biostatistics, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. *Correspondence: Assistant Professor of Urology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Tel: +989143511353. Email: farzinsoleimanzade@gmail.com. Received July 2020 & Accepted September 2020 ed to occur in order to adapt the body to the dehydrated state. Nevertheless, some studies show that in spite of these changes, there is no deterioration in renal func- tion in healthy individuals and even in some patients with chronic kidney disease.(6) However, there are still concerns about fluid restriction in people with chron- ic kidney disease. Some data, although not conclusive, suggest that fasting can alter the renal tubular system in people with chronic kidney disease.(7,8) Another issue is the direct effects of Ramadan fasting on urinary stone formation. In the available literature, controversial findings have been reported in this regard. Several studies have shown that fluid restriction and de- hydration increase the risk of urolithiasis.(9) Most stud- ies failed to find such a relationship.(10-14) In addition, the role of metabolic status has been sug- gested as a possible factor in the evaluation of lithogen- ic factors. For instance, the collection of some etiologic factors of stone formation may play a pathogenic role more than it was previously assumed.(15) Several studies have tried to declare the effect of Rama- dan fasting on urinary stone formation. However, most Urology Journal/Vol 18 No. 4/July-August 2021/ pp. 364-370. [DOI: 10.22037/uj.v16i7.6373] of them are methodologically weak with different study designs, various outcome measures, and conclusions. Considering the high incidence of fasting among Mus- lims and the fact that the characteristics of this matter have not been dealt with in depth, we decided to run a systematic review evaluating the effect of Ramadan fasting on urolithiasis. METHODS AND MATERIALS This systematic review was conducted in accordance with the JBI methodology for systematic review of prevalence evidence(16) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (17) to make sure the methods and reporting of data is comprehensive and transparent. The question of this review was as followed: "Does Ramadan fasting affect urinary stone formation or clin- ical manifestation in people who fast continuously dur- ing Ramadan?" Inclusion and Exclusion Criteria We included any study which evaluated people who fast uninterruptedly and compared them with non-fast- ing people or with themselves while they were not fast- ing. All observational studies including prospective and retrospective cohort, case-control, and cross-sectional studies were included in this review. Studies published in English from 1980 till the end of 2019 were consid- ered for inclusion in the current review. Exclusion criteria were as follows: 1) Fasting out of Ramadan conditions, 2. Non-comparative studies (re- views, case series, reports…) 3. Animal studies, 4. Patients with bladder stones (due to different nature of pathogenesis) and 5. Studies evaluating conditions that are only indirectly related to the stone formation or clin- ical manifestations of it (acid-base balance, changes in specific gravity…). The target population consists of people who fast con- tinuously during the month of Ramadan. Outcome measures included both clinically symptomat- ic presentation of stone disease (renal colic, obstructive uropathy, urinary retention…) and asymptomatic find- ing of evidence in favor of urolithiasis (imaging or lab- oratory findings). Search Strategy We searched PubMed, Embase, Scopus, ProQuest, Web of Science, and The Cochrane Library Pubmed database was searched using the following keywords: "fasting", "ramadan fasting", "ramazan fasting", "islam- ic fasting", "food abstinence", "fasting in Islam", the term ramadan was added to different terms used for uri- nary stones disease (urolithiasis/ urinary lithiasis, urine calculi/ calculus, kidney stone / stones and many other phrases offered via Mesh). For Embase a specific key- word set was used. We first included all of the studies form January 1980 until the end of 2019. We screened reference lists of included studies and review articles. The full search strategy for PubMed and Embase is pro- vided in Appendix I. Study selection Following the search, all identified citations were im- ported into EndNote X9.1 and duplicates were removed. Two independent reviewers (FS & HG) screened titles and abstracts for eligibility criteria of the review. The full text of potentially eligible studies was retrieved and assessed in detail against the inclusion criteria by the mentioned reviewers. Studies that did not meet the in- clusion criteria were excluded. Any disagreements be- tween the reviewers were resolved through discussion, or by referring to a third reviewer (MA). Assessment of methodological quality Two independent reviewers (FS & HS) critically ap- praised eligible studies at the study level using stand- ardized critical appraisal instruments from the Joanna Briggs Institute JBI Critical Appraisal Checklist for An- alytical Cross Sectional and/ or Case Control Studies. (Figure 2, 3) Any disagreements between the review- ers were resolved through discussion. The details of the study qualities are presented in Table 1. Data extraction Two independent reviewers extracted data from includ- ed studies using modified standardized JBI data extrac- tion tool.(16) The data extracted included populations, sample size, study methods, publication year, and re- gion of study, mean age, gender, and outcome measure- ment. The reviewers resolved disagreements through discussion. Extracted data from included studies are presented in Table 2. RESULTS Study inclusion Comprehensive electronic searching identified 181 studies. In the screening steps of title, abstract and full- text, two reviewers selected 106 studies, and finally 5 observational studies remained for critical appraising process. The PRISMA flowchart of this process is rep- resented Figure 1. Meta-analysis could not be performed because of heter- ogeneity in terms of methods, objectives, and findings. Among the included five studies, four of them evaluat- ed the occurrence rate of renal colic in Ramadan-fasting people, although in different methods. Characteristics of the included studies The characteristics of the included studies are summa- rized in Table 2. Norouzy, et al(18) in 2011 evaluated the number of pa- Fasting and kidney stone-Amjadi et al. Review 365 No. Authors Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 1 Norouzy, et al (2011) ☺ ☹ 😐 ☹ 😐 😐 ☹ ☺ - - 2 Al Mahayni, et al (2018) ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ - - 3 Basiri, et al (2004) ☹ ☹ 😐 😐 😐 😐 😐 ☺ - - 4 Cevik, et al (2016) ☺ ☺ ☺ ☺ 😐 😐 ☺ ☺ - - 5 Miladipour, et al (2012) ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ 😐 ☹ Table 1. Quality scoring results using JBI appraisal checklist for urolithiasis related studies* ☺: Low risk ☹: High risk 😐: Unclear risk *Description of questions in JBI Critical Appraisal Checklist for Analytical Cross Sectional Studies and Case-Control are listed in Figures 2 and 3. tients admitted with renal colic during various stages of peri-Ramadan month This was a prospective obser- vational study. They defined four stages of two-week periods starting two weeks before Ramadan (stage 1) and finishing two weeks after Ramadan (stage 4). The authors found that the occurrences of renal colic among all 610 patients in two major hospitals were increased significantly during the first two weeks of Ramadan (stage 2). However, the number of admissions de- creased during the last two weeks of Ramadan and two weeks after Ramadan (stage 3 and 4). They also noticed the mean room temperature for each group (27.7°C, 24.8°C, 23.5°C, and 21.2°C for stages 1 to 4 respec- tively). This is important especially when we face the results of other studies. Al Mahayni, et al(19) retrospectively evaluated 237 pa- tients admitted through the Emergency Room (ER) with a diagnosis of renal colic secondary to urinary stones over a 10-year period and compared Ramadan versus non-Ramadan months, as well as Ramadan in the sum- mer (between 41-45 degrees Celsius) versus in the win- ter (21-24 degrees Celsius) among these patients. They concluded that Ramadan fasting did not increase the risk for developing urinary stones compared to non-fasting Vol 18 No 4 July-August 2021 366 Table 2. Characteristics of included studies. No. Author Year Study Country Population Sample Subject Study Methods for Results ``` design size characteristics duration (months) Outcome measurement Male Females Age (mean) 2 weeks prior Symptoms of renal A significant 1 Norouzy A, 2011 Prospective Mashad/ Renal colic. 610 441 169 37.6 (range Ramadan till colic based on increase in et al, 2011 observational Iran due to urinary 15–85 years) 2 weeks after physician's clinical the incidence study tract stones Ramadan judgment. of ureteric colic during Ramadan. 2 Al Mahayni 2018 Retro- Riyadh/ Renal colic 237 178 59 45.8 1 Confirmed clinically Fasting in A, et al, 2018 spective Kingdom due to urinary and radiologically Ramadan of Saudi tract stones. (non-contrast CT scan) does not Arabia increase the risk for developing urinary stones compared to non-fasting months. Ramadan in summer may increase the risk of developing ureter stones compared to fasting in Ramadan during the winter. 3 Basiri, 2004 Retro- Varamin Renal Colic 574 398 176 36.4 1 Acute attack Higher et al, 2004 spective /Iran due to urinary of renal colic temperature tract stones. rather than fasting is a cause for ureteric colic. 4 Cevik Y, 2016 Prospective Turkey Renal Colic 176 112 64 40.47 2 Physician’s clinical No change et al, 2016 observational due to (range judgment according in visits study urinary tract 18-81 years) to classical clinical related to stones. features, history, renal colic and physical examination during CT in no definite Ramadan. diagnoses. . 5 Miladipour A, 2012 Case- Tehran 37 recurrent 57 57 - 41.66 1 Urine metabolite Fasting et al, 2012 Control /Iran calcium concentrations and during calculus supersaturations during Ramadan formers and fasting and non-fasting had different 20 with no periods in recurrent effects on history of calcium calculus total kidney calculi formers and healthy excretion and controls concentrtions of urinary precipitate and inhibitory factors contributing to calculus formation. Fasting and kidney stone-Amjadi et al. months. However, fasting in Ramadan during the sum- mer may increase the risk of developing ureteral stones compared to fasting in winter. They also mentioned that the possibility of finding a urinary stone in ureter during Ramadan is more likely than other locations of urinary system. Basiri, et al(11) evaluated monthly variations of renal colic in 574 patients in a 12-month period, 43 of which presented during Ramadan. They found that high tem- perature rather than fasting can leads to increased col- Review 367 Figure 1. PRISMA flow diagram of selectio Figure 2. JBI Critical Appraisal Checklist for Analytical Cross Sectional Studies. Fasting and kidney stone-Amjadi et al. icky pain episodes. There were seven lunar months with more than 43 presented patients. Cevik, et al(20), evaluated 176 patients with ureteric col- ic (89 before Ramadan, 87 in Ramadan) also showed that fasting did not change the number of ureteric col- ic visits. They also showed that despite some changes in urinary metabolites by fasting, there is not enough evidence that these changes increase urinary calculus formation. Miladpour, et al(12) evaluated biochemical laboratory findings of urine and blood samples as well as renal ultrasonography in 57 patients (37 recurrent calcium stone formers and 20 people without history of urolith- iasis) in fasting and non-fasting conditions. We should be cautious about the findings since changes in many of these tests cannot necessarily result in stone formation. However, some of the parameters like ultrasonography studies were objective means, directly addressing the stone. The authors found a number of effects on total excretion and concentrations of urinary precipitate and inhibitory elements but they concluded that enough ev- idence in favor of increased risk of calculus formation could not be found. DISCUSSION The studies evaluated for this systematic review are not sufficiently informative about the effects of Ramadan fasting on urinary stone disease. This lack of conclu- siveness was the result of different factors, some of which are discussed below: 1. Methodological diversity: the studies were quite different in their methods. Some are retrospec- tive and others prospective, with various focus points, which can affect the overall results. 2. Quality: No randomized clinical trials were available, which makes sense considering it is hardly feasible to randomize people in fasting and non-fasting groups None of our included studies met the good qual- ity characteristics of JBI checklist except in rare aspects (Table 1). 3. Study objectives: Four out of five studies used the frequency or monthly trend of acute renal colic, comparing non fasting condition with fasting as their main outcome. Although this can be one aspect of clin- ical manifestations, it is an oversimplification of a com- plex multifactorial process, considering the fact that stone formation does not necessarily result in renal col- Figure 3. JBI Critical Appraisal Checklist for Case-Control studies. Fasting and kidney stone-Amjadi et al. Vol 18 No 4 July-August 2021 368 ic in a given time frame. In other words, a small nidus of stone can be first formed in kidneys during the fasting period, turning to a visible, clinically important stone later, when it may not seem to be related to fasting. One other important aspect of choosing symptomatic stone passage as a means for evaluation of stone forma- tion is the possibility of missing “asymptomatic stone passages". D’Costa el al,(21) showed that among a group of patients with asymptomatic small kidney stones, at 5 years there was a CT scan-detected stone passage rate of 51 percent, only about half of which were accompa- nied by symptoms. This finding means that small stones may pass without obvious clinical symptoms and the stone formation rate can be underestimated using ure- teric colic as the outcome of interest. 4. Seasonal changes in Ramadan: since the lunar year is ten days shorter than solar year, month of Ram- adan lies in different seasons during a long time frame. When it lies in summer, especially in hot climate, longer day hours and higher temperature may be related to a higher risk of dehydration and resultant stone formation rate. This is a possibility not appropriately addressed in all of the studies included. 5. Heterogeneous results: Even among these rare studies, the results are not homogenous. Norou- zy et al,(18) showed a significant difference in clinical presentation of renal colic during the first two weeks of Ramadan compared to the other stages before and after this period. This increase-decrease pattern was the same in two different hospitals evaluated in this study, showing that possibly this is not a random finding. Oth- ers however, could not find such relationship. Instead, they found that the hot climate is much more likely than Ramadan fasting itself to affect urolithiasis. 5. Ignoring other possible factors: In the meantime, the effect of combining two or more risk-producing con- ditions on urinary stone disease has not been properly identified in the literature. As an instance, it is not clear whether Ramadan fasting in summer and hot climate ar- eas, would add an additional risk of stone formation to the risk attributed to the climate only? Does coincidence of polycystic kidney disease, severe hypertension, dia- betic nephropathy or different levels of chronic kidney disease PLUS fasting in Ramadan, apply an additional risk of calculus formation to the kidneys? CONCLUSIONS The effect of combining two or more risk-producing conditions on urinary stone disease has not been proper- ly identified in the studies. Due to the poor quality of the current literature as discussed, it is impossible to form a generalized opinion on whether fasting in Ramadan affect the stone formation. For instance, it is not clear whether Ramadan fasting in summer and hot climate areas, would add an additional risk of stone formation to the risk attributed to the climate only? Does coin- cidence of polycystic kidney disease, severe hyperten- sion, diabetic nephropathy or different levels of chronic kidney disease in addition to fasting in Ramadan, apply an additional risk of calculus formation to the kidneys? This issues can be addresses in future studies. ACKNOWLEDGEMENT We hereby express our thankfulness to Zahra Golmarzi Asl for her kind help. APPENDIX https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryFiles/downloadPublic/10 REFERENCES 1. 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