Ketogenic Diet: History
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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).

  • ketogenic diet
  • kidney stones
  • nephrolithiasis
  • epidemiology
  • meta-analysis
  • systematic review

1. 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 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 anti-seizure 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].
Multiple formulations of the ketogenic diet are currently available, including the classic keto diet, low glycemic index diet (LGID), medium-chain triglyceride diet (MCT), and modified Atkins diet. These diets differ in the proportions of lipid, carbohydrate, and protein contents [10][13][14][15]. Despite potential advantages, the ketogenic diet has multiple adverse effects. During the first four-week period, nausea, vomiting, and diarrhea are particularly common with the medium-chain triglyceride diet [16][17][18], posing a risk for acute kidney injury, hyponatremia, hypomagnesemia, hypercalciuria, hyperuricemia, and metabolic acidosis [19][20][21]. Long-term adverse effects of the ketogenic diet, including osteopenia, risk of bone fractures, alterations in vitamin D levels, are well reported [22][23][24]. Increased risk for kidney stones is well described in patients using the ketogenic diet for over a 2 year period [17][20][25][26], with complications such as obstructive uropathy, acute kidney injury, and chronic kidney disease [27][28][29].
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.

2. Incidence and Characteristics of Kidney Stones in Patients on Ketogenic Diet

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 [32].

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 [32]. 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][33][34][35][36][37][38]. A more generous amount of free calcium is available for stone formation in a low-citrate environment [33][39]. 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 [33]. Obesity, insulin resistance, and an animal-protein diet are associated with low urine pH [40]. The uric acid stone may act as a nidus for calcium-based nephrolithiasis formation [33]. Furthermore, fluid intake restriction is traditionally applied to children receiving the ketogenic diet, making them susceptible to stone formation [33].

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][35][38]. Genetic polymorphisms in transporters, such as renal sodium citrate cotransporter, is a known risk factor in recurrent stone formers [41][42]. 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 [43]. 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 [40]. The digestion of animal protein produces a transient acidic environment, which results in a lower urine pH, promoting the precipitation of uric stones [40]. 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 [44]. It is also recommended that patients with symptomatic hypercalcemia, hyperuricosuric calcium urolithiasis, and urate nephropathy should be prescribed a urate-lowering agent [40]. 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 [45][46]. Modification of the diet regimen to allow small, frequent meals might help decrease gastrointestinal side effects and avoid volume depletion [47]. Screening for underlying metabolic disorders should be considered before initiation of a ketogenic diet to help avoid substantial acidosis [48]. 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 [49]. 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 [50]. 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][50]. 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 [51].

3. 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.

This entry is adapted from the peer-reviewed paper 10.3390/diseases9020039


  1. Paoli, A.; Cenci, L.; Grimaldi, K. Effect of ketogenic mediterranean diet with phytoextracts and low carbohydrates/high-protein meals on weight, cardiovascular risk factors, body composition and diet compliance in Italian council employees. Nutr. J. 2011, 10, 112.
  2. Hawkes, C.P.; Roy, S.M.; Dekelbab, B.; Frazier, B.; Grover, M.; Haidet, J.; Listman, J.; Madsen, S.; Roan, M.; Rodd, C.; et al. Hypercalcemia in Children Using the Ketogenic Diet: A Multicenter Study. J. Clin. Endocrinol. Metab. 2021, 106, e485–e495.
  3. Sinha, S.R.; Kossoff, E.H. The Ketogenic Diet. Neurology 2005, 11, 161–170.
  4. Stafstrom, C.E.; Spencer, S. The ketogenic diet: A therapy in search of an explanation. Neurology 2000, 54, 282.
  5. Hartman, A.L.; Stafstrom, C.E. Harnessing the power of metabolism for seizure prevention: Focus on dietary treatments. Epilepsy Behav. 2013, 26, 266–272.
  6. Nylen, K.; Likhodii, S.; Burnham, W.M. The ketogenic diet: Proposed mechanisms of action. Neurotherapeutics 2009, 6, 402–405.
  7. Klesges, R.C.; Ward, K.D.; Shelton, M.L.; Applegate, W.B.; Cantler, E.D.; Palmieri, G.M.A.; Harmon, K.; Davis, J. Changes in Bone Mineral Content in Male Athletes. JAMA 1996, 276, 226–230.
  8. Wheless, J.W. History of the ketogenic diet. Epilepsia 2008, 49, 3–5.
  9. Kossoff, E.H.; Zupec-Kania, B.A.; Amark, P.E.; Ballaban-Gil, K.R.; Bergqvist, A.G.C.; Blackford, R.; Buchhalter, J.R.; Caraballo, R.H.; Cross, J.H.; Dahlin, M.G.; et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia 2009, 50, 304–317.
  10. Kossoff, E.H.; Zupec-Kania, B.A.; Rho, J.M. Ketogenic Diets: An Update for Child Neurologists. J. Child Neurol. 2009, 24, 979–988.
  11. Davidson, T.; Hargrave, S.; Swithers, S.; Sample, C.; Fu, X.; Kinzig, K.; Zheng, W. Inter-relationships among diet, obesity and hippocampal-dependent cognitive function. Neuroscience 2013, 253, 110–122.
  12. Freedland, S.J.; Mavropoulos, J.; Wang, A.; Darshan, M.; Demark-Wahnefried, W.; Aronson, W.J.; Cohen, P.; Hwang, D.; Peterson, B.; Fields, T.; et al. Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 2008, 68, 11–19.
  13. Klepper, J.; Leiendecker, B. GLUT1 deficiency syndrome—2007 update. Dev. Med. Child Neurol. 2007, 49, 707–716.
  14. Wexler, I.D.; Hemalatha, S.G.; McConnell, J.; Buist, N.; Dahl, H.-H.M.; Berry, S.A.; Cederbaum, S.D.; Patel, M.S.; Kerr, D.S. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets: Studies in patients with identical mutations. Neurology 1997, 49, 1655–1661.
  15. Meira, I.D.; Romão, T.T.; Prado, H.J.P.D.; Krüger, L.T.; Pires, M.E.P.; Da Conceição, P.O. Ketogenic Diet and Epilepsy: What We Know So Far. Front. Neurosci. 2019, 13, 5.
  16. Freeman, J.M.; Kelly, M.T.; Freeman, J.B. The Epilepsy Diet Treatment: An Introduction to the Ketogenic Diet; Demos Vermande: New York, NY, USA, 1996.
  17. Liu, Y.M.; Wang, H.S. Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy and a comparison with other ketogenic diets. Biomed. J. 2013, 36, 9–15.
  18. Tanchoco, C.C.; Cruz, A.J.; Rogaccion, J.M.; Casem, R.S.; Rodriguez, M.P.; Orense, C.L.; Hermosura, L.C. Diet supplemented with MCT oil in the management of childhood diarrhea. Asia Pac. J. Clin. Nutr. 2007, 16, 286–292.
  19. Ballaban-Gil, K.; Callahan, C.; O’Dell, C.; Pappo, M.; Moshe, S.; Shinnar, S. Complications of the Ketogenic Diet. Epilepsia 1998, 39, 744–748.
  20. Bach, A.C.; Babayan, V.K. Medium-chain triglycerides: An update. Am. J. Clin. Nutr. 1982, 36, 950–962.
  21. Chesney, D.; Brouhard, B.H.; Wyllie, E.; Powaski, K. Biochemical abnormalities of the ketogenic diet in children. Clin. Pediatr. 1999, 38, 107–109.
  22. Bertoli, S.; Trentani, C.; Ferraris, C.; De Giorgis, V.; Veggiotti, P.; Tagliabue, A. Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: A case series. Nutrition 2014, 30, 726–728.
  23. Bergqvist, A.C.; Schall, J.I.; Stallings, V.A. Vitamin D Status in Children with Intractable Epilepsy, and Impact of the Ketogenic Diet. Epilepsia 2007, 48, 66–71.
  24. Bergqvist, A.G.C.; Schall, J.; Stallings, V.; Zemel, B.S. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am. J. Clin. Nutr. 2008, 88, 1678–1684.
  25. Choi, J.N.; Song, J.E.; Shin, J.I.; Kim, H.D.; Kim, M.J.; Lee, J.S. Renal stone associated with the ketogenic diet in a 5-year old girl with intractable epilepsy. Yonsei Med. J. 2010, 51, 457–459.
  26. Kielb, S.; Koo, H.P.; Bloom, D.A.; Faerber, G.J. Nephrolithiasis associated with the ketogenic diet. J. Urol. 2000, 164, 464–466.
  27. Rule, A.D.; Bergstralh, E.J.; Melton, L.J.; Li, X.; Weaver, A.L.; Lieske, J.C. Kidney Stones and the Risk for Chronic Kidney Disease. Clin. J. Am. Soc. Nephrol. 2009, 4, 804–811.
  28. El-Zoghby, Z.M.; Lieske, J.C.; Foley, R.N.; Bergstralh, E.J.; Li, X.; Melton, L.J.; Krambeck, A.E.; Rule, A.D. Urolithiasis and the Risk of ESRD. Clin. J. Am. Soc. Nephrol. 2012, 7, 1409–1415.
  29. Thongprayoon, C.; Hansrivijit, P.; Kovvuru, K.; Kanduri, S.R.; Torres-Ortiz, A.; Acharya, P.; Gonzalez-Suarez, M.L.; Kaewput, W.; Bathini, T.; Cheungpasitporn, W. Diagnostics, Risk Factors, Treatment and Outcomes of Acute Kidney Injury in a New Paradigm. J. Clin. Med. 2020, 9, 1104.
  30. Paul, E.; Conant, K.D.; Dunne, I.E.; Pfeifer, H.H.; Lyczkowski, D.A.; Linshaw, M.A.; Thiele, E.A. Urolithiasis on the ketogenic diet with concurrent topiramate or zonisamide therapy. Epilepsy Res. 2010, 90, 151–156.
  31. Kang, H.C.; Kim, Y.J.; Kim, N.W.; Kim, H.D. Efficacy and Safety of the Ketogenic Diet for Intractable Childhood Epilepsy: Korean Multicentric Experience. Epilepsia 2005, 46, 272–279.
  32. Curhan, G.C. Epidemiology of Stone Disease. Urol. Clin. N. Am. 2007, 34, 287–293.
  33. Bushinsky, D.A.; Coe, F.L.; Moe, O.W. Nephrolithiasis. Brenner Rector’s Kidney 2012, 9, 1455–1507.
  34. Dunn-Geier, J.; Ho, H.H.; Auersperg, E.; Doyle, D.; Eaves, L.; Orrbine, E.; Whiting, S. Effect of secretin on children with autism: A randomized controlled trial. Dev. Med. Child Neurol. 2007, 42, 796–802.
  35. Chow, K.; Dixon, J.; Gilpin, S.; Kavanagh, J.P.; Rao, P.N. Citrate inhibits growth of residual fragments in an in vitro model of calcium oxalate renal stones. Kidney Int. 2004, 65, 1724–1730.
  36. Rudman, D.; Kunter, M.H.; Redd, S.C.; Waters, W.C.; Gerron, G.G.; Bleier, J. Hypocitraturia in Calcium Nephrolithiasis. J. Clin. Endocrinol. Metab. 1982, 55, 1052–1057.
  37. Pak, C.Y. Etiology and Treatment of Urolithiasis. Am. J. Kidney Dis. 1991, 18, 624–637.
  38. Pak, C.Y.; Poindexter, J.R.; Adams-Huet, B.; Pearle, M.S. Predictive value of kidney stone composition in the detection of metabolic abnormalities. Am. J. Med. 2003, 115, 26–32.
  39. Curhan, G.; Taylor, E. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008, 73, 489–496.
  40. Ngo, T.C.; Assimos, D.G. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev. Urol. 2007, 9, 17–27.
  41. Okamoto, N.; Aruga, S.; Matsuzaki, S.; Takahashi, S.; Matsushita, K.; Kitamura, T. Associations between renal sodium-citrate cotransporter (hNaDC-1) gene polymorphism and urinary citrate excretion in recurrent renal calcium stone formers and normal controls. Int. J. Urol. 2007, 14, 344–349.
  42. Nicar, M.J.; Skurla, C.; Sakhaee, K.; Pak, C.Y. Low urinary citrate excretion in nephrolithiasis. Urology 1983, 21, 8–14.
  43. McNally, M.A.; Pyzik, P.L.; Rubenstein, J.E.; Hamdy, R.F.; Kossoff, E.H. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet. Pediatrics 2009, 124, e300–e304.
  44. Siener, R.; Hesse, A. The effect of a vegetarian and different omnivorous diets on urinary risk factors for uric acid stone formation. Eur. J. Nutr. 2003, 42, 332–337.
  45. Agarwal, N.; Arkilo, D.; Farooq, O.; Gillogly, C.; Kavak, K.S.; Weinstock, A. Ketogenic diet: Predictors of seizure control. SAGE Open Med. 2017, 5.
  46. Wirrell, E.C.; Darwish, H.Z.; Williams-Dyjur, C.; Blackman, M.; Lange, V. Is a Fast Necessary When Initiating the Ketogenic Diet? J. Child Neurol. 2002, 17, 179–182.
  47. Zupec-Kania, B.A.; Spellman, E. An Overview of the Ketogenic Diet for Pediatric Epilepsy. Nutr. Clin. Pract. 2008, 23, 589–596.
  48. DeVivo, D.C.; Haymond, M.W.; Leckie, M.P.; Bussmann, Y.L.; McDougal, J.D.B.; Pagliara, A.S. The Clinical and Biochemical Implications of Pyruvate Carboxylase Deficiency. J. Clin. Endocrinol. Metab. 1977, 45, 1281–1296.
  49. Rendina, D.; De Filippo, G.; Iannuzzo, G.; Abate, V.; Strazzullo, P.; Falchetti, A. Idiopathic Osteoporosis and Nephrolithiasis: Two Sides of the Same Coin? Int. J. Mol. Sci. 2020, 21, 8183.
  50. Merlotti, D.; Cosso, R.; Eller-Vainicher, C.; Vescini, F.; Chiodini, I.; Gennari, L.; Falchetti, A. Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on This Issue. Int. J. Mol. Sci. 2021, 22, 435.
  51. Aronica, L.; Volek, J.; Poff, A.; D’Agostino, D.P. Genetic variants for personalised management of very low carbohydrate ketogenic diets. BMJ Nutr. Prev. Health 2020, 3, 363–373.
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