Incidence and Characteristics of Kidney Stones in Patients on Ketogenic Diet: A Systematic Review and Meta-Analysis

Very-low-carbohydrate diets or ketogenic diets are frequently used for weight loss in adults and as a therapy for epilepsy in children. The incidence and characteristics of kidney stones in patients on ketogenic diets are not well studied. Methods: A systematic literature search was performed, using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from the databases’ inception through April 2020. Observational studies or clinical trials that provide data on the incidence and/or types of kidney stones in patients on ketogenic diets were included. We applied a random-effects model to estimate the incidence of kidney stones. Results: A total of 36 studies with 2795 patients on ketogenic diets were enrolled. The estimated pooled incidence of kidney stones was 5.9% (95% CI, 4.6–7.6%, I2 = 47%) in patients on ketogenic diets at a mean follow-up time of 3.7 +/− 2.9 years. Subgroup analyses demonstrated the estimated pooled incidence of kidney stones of 5.8% (95% CI, 4.4–7.5%, I2 = 49%) in children and 7.9% (95% CI, 2.8–20.1%, I2 = 29%) in adults, respectively. Within reported studies, 48.7% (95% CI, 33.2–64.6%) of kidney stones were uric stones, 36.5% (95% CI, 10.6–73.6%) were calcium-based (CaOx/CaP) stones, and 27.8% (95% CI, 12.1–51.9%) were mixed uric acid and calcium-based stones, respectively. Conclusions: The estimated incidence of kidney stones in patients on ketogenic diets is 5.9%. Its incidence is approximately 5.8% in children and 7.9% in adults. Uric acid stones are the most prevalent kidney stones in patients on ketogenic diets followed by calcium-based stones. These findings may impact the prevention and clinical management of kidney stones in patients on ketogenic diets.


Introduction
The ketogenic diet, initially introduced in the early nineteenth century, refers to a diet pattern that is low in carbohydrates and high in fat with a moderate proportion of protein (1.2-1.5 g/kg) [1,2]. The ketogenic diet increases the oxidation of fatty acids and ketone bodies production-creating a state of ketosis and mild acidosis [3,4]. A ketogenic diet leads to glycolysis inhibition, inhibits glutamatergic synaptic transmission, and assists in weight Diseases 2021, 9,39 2 of 13 loss [5, 6], making it popular not only for patients with obesity or metabolic syndrome, but even for athletes, both professional and amateur [7]. Ketone bodies (acetate, aceto-acetate, and beta-hydroxybutyrate) have been shown to prevent recurrent seizures [8][9][10], hence are prescribed for children with intractable seizures. However, the mechanism of the antiseizure effects of ketone bodies is not well understood. The ketogenic diet may also have a protective effect against cognitive impairment [11] and malignancy [12]. Indications for the ketogenic diet have been extended to include glucose-1 transporter deficiency syndrome and pyruvate dehydrogenase deficiency disorders [13,14].
The incidence of kidney stones among patients on the ketogenic diet ranges from 3% to 10% [20,30,31], compared to one in several thousand in the general population [17,24]. We performed a meta-analysis on the incidence and characteristics of kidney stones in patients on the ketogenic diet to better understand the kidney stones' burden and pathophysiology in this population.

Search Strategies
A comprehensive search of several databases from each database's inception to 3 May 2019 was conducted. The databases included OVID MEDLINE (1946 to April 2020), EMBASE (1988 to April 2020), and the Cochrane Database of Systematic Reviews (database inception to April 2020). The systematic literature review was conducted independently by two investigators (P.A. and C.A.), using the search strategy that consolidated the terms of ('ketogenic diet' OR 'keto diet' OR 'atkins diet' OR 'low carb diet' OR 'low carbohydrate diet') AND (nephrolithiasis OR 'kidney stone' OR 'kidney stones'). The actual strategy listing all search terms used is available in the online Supplementary Materials. There were no restrictions on language, sample size, or study duration. This study was conducted by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (online Supplementary Materials) [32].

Study Selection
Eligible studies must be clinical trials, observational studies (cohort, case-control, or cross-sectional studies) that reported incidence and characteristics of kidney stones in patients on ketogenic diets. Retrieved articles were individually reviewed for eligibility by the two investigators (P.A. and C.A.). Discrepancies were addressed and resolved by third investigator (W.C.). Inclusion was not limited by language, age, sample size, or study duration.

Data Extraction
The following data were extracted: first author name, year of publication, number of patients, duration of follow-up, description of ketogenic diet, mean age, sex, incidence of kidney stones, type of kidney stones, and time to diagnosis of kidney stones after ketogenic diet consumption. The primary outcome included the incidence of kidney stones.

Data Synthesis and Statistical Analysis
We calculated the pooled estimated incidence of kidney stones among patients on the ketogenic diet. The pre-specified subgroup analysis based on age groups (pediatrics and adults) was performed. A random-effects model was used due to the expected clinical heterogeneity in the included populations [33]. All pooled estimates were shown with 95% confidence intervals (CIs). Heterogeneity among effect sizes estimated by individual studies was described with the I 2 statistic and the chi-square test. A value of I 2 of 0% to 25% represents insignificant heterogeneity, 26% to 50% low heterogeneity, 51% to 75% moderate heterogeneity and 76% to 100%, high heterogeneity [34].
Publication bias was evaluated using the Egger test [35]. A p-value of less than 0.05 indicates the presence of publication bias. The meta-analysis was performed by the Comprehensive Meta-Analysis 3.3 software (Biostat Inc, Englewood, NJ, USA). The data for this meta-analysis are publicly available through the Open Science Framework on 25 September 2020 (URL: https://osf.io/2gtk3/ (accessed on 25 September 2020)).

Results
A total of 221 potentially relevant articles were identified and screened. Fifty-one articles were assessed in detail of which 36 studies with 2795 patients on ketogenic diets were enrolled in our meta-analysis ( Figure 1 and Table 1). The definitions and reported adverse effects observed in ketogenic diets in different studies are shown in Table 2. Abbreviations: -KGD-ketogenic diet; MAD-modified Atkins diet; MCT-medium chain triglyceride diet; NR-nonreport; LGID-low glycemic index diet.      Abbreviations: KGD-ketogenic diet; MAD-modified Atkins diet; MCT-medium chain triglyceride diet; NR-non-report; LGID-low glycemic index diet.

Evaluation for Publication Bias
Using Egger's regression asymmetry tests, there was no significant publication bias found in this meta-analysis. The Egger's regression test demonstrated no significant publication bias in all analyses (p > 0.05).

Discussion
Our analysis reports a pooled incidence of kidney stones at 5.6% in patients treated with a ketogenic diet after four years. The incidence of nephrolithiasis in the general population is reported at 0.3% per year in men and 0.25% per year in women [72]. In our study, the incidence of kidney stones is identical in children and adults. This finding contradicts the hypothesis that children are more susceptible to kidney stone formation due to extended treatment duration with the ketogenic diet, small renal tubular lumen, and relatively less renal reserve. However, studies included in this analysis did not report the recurrence of kidney stones; it is possible children may be predisposed to recurrent kidney stones due to prolonged exposure to the ketogenic diet. More studies are required to understand the risk of recurrent kidney stones with the ketogenic diet.
Uric acid stones are the most common stones in patients receiving the ketogenic diet, followed by calcium-based stones and uric acid-calcium mixed stones. In contrast, calcium oxalate stones are the most common stones in the general population [72]. The

Evaluation for Publication Bias
Using Egger's regression asymmetry tests, there was no significant publication bias found in this meta-analysis. The Egger's regression test demonstrated no significant publication bias in all analyses (p > 0.05).

Discussion
Our analysis reports a pooled incidence of kidney stones at 5.6% in patients treated with a ketogenic diet after four years. The incidence of nephrolithiasis in the general population is reported at 0.3% per year in men and 0.25% per year in women [72]. In our study, the incidence of kidney stones is identical in children and adults. This finding contradicts the hypothesis that children are more susceptible to kidney stone formation due to extended treatment duration with the ketogenic diet, small renal tubular lumen, and relatively less renal reserve. However, studies included in this analysis did not report the recurrence of kidney stones; it is possible children may be predisposed to recurrent kidney stones due to prolonged exposure to the ketogenic diet. More studies are required to understand the risk of recurrent kidney stones with the ketogenic diet.
Uric acid stones are the most common stones in patients receiving the ketogenic diet, followed by calcium-based stones and uric acid-calcium mixed stones. In contrast, calcium oxalate stones are the most common stones in the general population [72]. The exact mechanism of nephrolithiasis following the ketogenic diet is unclear. However, it is likely related to hypocitraturia and acidosis, common in people consuming a high-protein and low-alkali diet [20]. Acidosis contributes to significant reabsorption of citrate in the proximal tubule, further contributing to hypocitraturia [25,[73][74][75][76][77][78]. A more generous amount of free calcium is available for stone formation in a low-citrate environment [73,79]. Chronic acidosis also leads to demineralization of the bone and increased calcium excretion [17,20]. Hypercalciuria, immobilization, anti-epileptic drugs, and fat malabsorption further precipitate urinary calcium. Moreover, the low urine pH seen in patients with a low-alkali diet contributes to uric acid crystals [73]. Obesity, insulin resistance, and an animal-protein diet are associated with low urine pH [80]. The uric acid stone may act as a nidus for calcium-based nephrolithiasis formation [73]. Furthermore, fluid intake restriction is traditionally applied to children receiving the ketogenic diet, making them susceptible to stone formation [73].
Potential benefits of urine alkalization with oral potassium citrate in children with a urine calcium to creatinine ratio of >0.20 mg/mg to prevent kidney stone formation is well reported [20,25,75,78]. Genetic polymorphisms in transporters, such as renal sodium citrate cotransporter, is a known risk factor in recurrent stone formers [81,82]. McNally et al. reported that the empiric use of oral citrate in children treated with a classic ketogenic diet led to a reduction in the incidence of kidney stones from 6.75% to 0.9% without an increase in adverse effects [67]. The international ketogenic diet study group agreed that oral citrates appear to prevent kidney stones; however, there was mixed opinion on its empiric use (class III) [9]. The consensus statement is unchanged since 2009 due to the lack of new evidence. Hence, we need a well-designed study to analyze the empiric use of urine alkalization therapy. A ketogenic diet is generally prescribed for weight loss in adults, who require a shorter duration of therapy; the empiric use of oral citrates may not be necessary. However, this remains to be elucidated by future studies.
Purine-rich foods (red meat, fish, poultry, beer, and legumes) increase the uric acid load [80]. The digestion of animal protein produces a transient acidic environment, which results in a lower urine pH, promoting the precipitation of uric stones [80]. Since uric stones are the most common stones in patients receiving a ketogenic diet, switching from animal proteins to plant-based proteins results in lower uric acid excretion, but, sequentially, lower uric acid stone formation is unclear. Siener et al. reported that patients consuming a balanced diet of vegetables and animal proteins had higher urine pH and urine uric acid concentration than those on a typical western diet [83]. It is also recommended that patients with symptomatic hypercalcemia, hyperuricosuric calcium urolithiasis, and urate nephropathy should be prescribed a urate-lowering agent [80]. However, empiric use of xanthine oxidase inhibitors in patients on a ketogenic diet requires further investigation.
Other measures to mitigate the risk of renal stones include liberalizing fluid intake and avoiding the initial fasting phase at the start of ketogenic diets [84,85]. Modification of the diet regimen to allow small, frequent meals might help decrease gastrointestinal side effects and avoid volume depletion [86]. Screening for underlying metabolic disorders should be considered before initiation of a ketogenic diet to help avoid substantial acidosis [87]. Considering the long-term risk of bone fractures and osteopenia, the 2018 international ketogenic diet group recommended periodic DEXA scan screening for evaluation of bone mineral density [9]. Epidemiological studies have shown a temporal relationship between idiopathic osteoporosis and kidney stones. In addition, changing dietary patterns, including the ketogenic diet, could possibly be an important environmental trigger in the association, as well [88]. Bone health should be monitored closely in patients on the ketogenic diet and more clinical trials are needed to further define the negative impacts on bone health [89]. Although prophylactic calcium and vitamin D is recommended in all people on the ketogenic diet for bone health [23,24], athletes with dermal calcium loss during exercise/sweating and obese subjects restricting dairy are at further risk of worsening bone health if not on adequate calcium supplements [7,89]. However, given the reported risk of nephrolithiasis from hypercalciuria, supplementation remains a challenge [20,25]. Periodic urine chemistry analyses to measure the calcium to creatinine ratio, calcium, citrate, and oxalate can help identify patients at risk for kidney stone formation, and timely referral to a nephrologist should be considered. Patients with a family history of nephrolithiasis should be screened before starting a ketogenic diet due to their higher risk for stone formation.
In the era of precision medicine, further studies are needed to understand the use of genetic variants to further personalize management, even in the dietary therapy field [90]. Our study has the following limitations. First, the observational studies included in the analysis are susceptible to shortcomings inherent to the design. In addition, sources of heterogeneity could be due to differences in patient population and definitions of ketogenic diet as described in Table 2. Second, important risk factors, such as family history of nephrolithiasis, physical activity, exposure to sunlight, presence of ketone bodies in the blood or urine and environmental exposure, were not mentioned in the included studies. Third, recurrent kidney stones are not differentiated from the first episodes; recurrent kidney stones might be more common in children. Fourth, the glomerular filtration rate decline was not the primary outcome in most of the included studies. Fifth, the pooled sample size for adults is smaller than children. Lastly, data on the estimated incidence of kidney stones in elderly and CKD patients on ketogenic diets were limited.

Conclusions
In conclusion, the estimated incidence of kidney stones in patients on ketogenic diets is 5.6%, which is comparable among adults and children. Uric acid stones are the most prevalent kidney stones in patients treated with ketogenic diets, followed by calcium-based stones. These findings may impact the prevention and management of kidney stones in patients treated with ketogenic diets.

Supplementary Materials:
The following are available on https://www.mdpi.com/article/10.339 0/diseases9020039/s1, the actual strategy listing all search terms; the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.