Let Food Be Thy Medicine

“Let food be thy medicine” is a quote attributed to Hippocrates (400BC), who recognized fasting as the only effective therapy against epilepsy, suggesting that dietary interventions hold potential for treating human diseases. In 1921, Russel Wilder was the first to propose that a ketone-generating diet could be as effective as fasting for treating epilepsy, and he coined the term “ketogenic diet.”¹

The classic ketogenic diet incorporates a 4:1 ratio of fat to protein plus carbohydrates and provides 90% of the total calories as fat. Because of its severe carbohydrate restriction, the classical ketogenic diet is unpalatable and challenging to follow, leading to the development of several modified versions. The modified Atkins diet shares food choices with the classic ketogenic diet but has a less strict ketogenic ratio (ranging from 1:1 to 1.5:1), making it easier to adhere to. Nevertheless, clinical evidence supports the efficacy of modified Atkins diet in children with refractory epilepsy.²

In recent decades, the potential beneficial effects of the ketogenic diet have garnered extensive interest for various diseases, including obesity, autoimmune conditions, cancers, and metabolic and neurodegenerative disorders.² However, the existing evidence regarding the use of ketogenic diet in the context of kidney disease is still limited.³ Potential side effects, such as dyslipidemia, lower intake of dietary fibers, metabolic acidosis, and a higher risk of nephrolithiasis, have raised concerns, which currently preclude the routine recommendation of ketogenic diet for individuals with CKD.⁴

In this issue of JASN, Bellomo et al. report on the effectiveness of ketogenic diet in addressing the kidney phenotype of cystinosis.⁵ Cystinosis (OMIM 219800) is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, which encodes the lysosomal membrane protein cystinosin. Cystinosin functions as a cystine-proton symporter, transporting the amino acid cystine out of the lysosome. Cystinosin deficiency leads to the accumulation of cystine within the lysosomes, which is the key biochemical feature of cystinosis.⁶

Although cystinosin is ubiquitously expressed, the disease primarily affects the kidneys. In its infantile form, cystinosis manifests as renal Fanconi syndrome within the first year of life and progresses to end stage kidney failure if left untreated. Advances in KRT for children have revealed that cystinosis also affects most other organs, leading to ocular, endocrine, muscular, and neurological complications.⁶

Since the 1990s, patients with cystinosis have been routinely treated with cystine-depleting drug cysteamine, which was proven to delay the progression of both kidney and extrarenal diseases. However, cysteamine does not cure cystinosis and is associated with bothersome side effects, such as halitosis and gastrointestinal complaints.⁶ As a result, the search for novel therapies for cystinosis is ongoing.

The rationale for testing ketogenic diet in cystinosis was based on mechanistic studies in other diseases showing that it can reduce oxidative stress, prevent mitochondrial damage, and mitigate tissue inflammation and fibrosis.⁵ In the initial experiment by Bellomo et al., cystinosis mice were treated with either a standard diet or a ketogenic diet from 3 to 12 months of age. The outcome measures included growth, features of Fanconi syndrome such as polyuria, tubular proteinuria, glucosuria, and aminoaciduria, as well as morphological changes in kidney tissue. The results revealed a remarkable effect of the ketogenic diet in treated animals. While features of Fanconi syndrome became evident in animals on a standard diet starting from 6 months of age, those on the ketogenic diet had no proximal tubular dysfunction. Moreover, kidney tissue was preserved, with restoration of proximal tubule morphology, prevention of apoptosis, normalization of autophagy markers, and the complete absence of fibrosis or inflammatory cell infiltrate, which were observed in animals on the standard diet. Unexpectedly, the cystine content in kidney tissue was also reduced by the ketogenic diet. Although some anecdotal reports in humans suggest that cysteamine can prevent Fanconi syndrome when started shortly after birth,⁷ the drug fails to reverse Fanconi syndrome once it is established. Excitingly, the ketogenic diet, even when applied after the onset of Fanconi syndrome at 6 months, could mitigate proximal tubular dysfunction. Finally, the authors validated their findings by applying the ketogenic diet to a cystinosis rat model. Compared with mice, cystinosis rats exhibit more pronounced Fanconi syndrome, which develops earlier, at approximately 3–4 months of age. Although the effect in rats treated from 2 to 8 months was less dramatic, the ketogenic diet was still able to prevent the development of Fanconi syndrome to a significant extent.

The pathogenesis of cystinosis is complex and not yet fully understood.⁸ Cystinosin, located on the lysosomal membrane, interacts with other proteins and likely has additional cellular functions beyond cystine transport, such as nutrient sensing and mammalian target of rapamycin signaling.⁸ The authors attempted to gain insights into the mechanism of action of the ketogenic diet on the cellular phenotypes of cystinosis by performing a transcriptomic analysis of kidney tissue harvested from 3-month-old cystinosis mice that had been on the ketogenic diet for 1 month. Although this analysis provided some mechanistic clues, showing improved expression of genes involved in mitochondrial, peroxisomal, and lipid metabolism in the ketogenic diet–treated animals, it did not fully elucidate the underlying mechanisms.

Recent comprehensive reviews highlighted the complex metabolic reprogramming induced by the ketogenic diet, which holds therapeutic potential for various diseases.^2,3 The ketone bodies (β-hydroxybutyrate and acetoacetate) produced as a result of the ketogenic diet serve as a more efficient energy source than glucose, metabolizing faster to acetyl-CoA entering directly into the tricarboxylic acid cycle, thus bypassing the glycolytic pathway. Consequently, ketone bodies promote mitochondrial oxidative metabolism.^2,3 This mechanism may contribute to the ketogenic diet's ability to enhance proximal tubule function in cystinosis because this nephron segment heavily relies on mitochondrial ATP production.⁹ Moreover, the healthy proximal tubule has gluconeogenic capacity and preferentially uses fatty acid oxidation to generate ATP because this energy source yields three-fold more ATP than glucose metabolism.⁹ Therefore, the increased fatty acid availability in the ketogenic diet may directly supply energy to the proximal tubule, which is compromised in cystinosis. In addition, β-hydroxybutyrate is increasingly recognized as an endogenous signaling molecule with antioxidant and anti-inflammatory properties, which may positively influence the altered metabolism in cystinosis cells (Figure 1).

Figure 1.

Potential effect of the ketogenic diet on the cellular phenotype of cystinosis. The key cellular phenotypes of cystinosis include lysosomal cystine accumulation, mitochondrial dysfunction resulting in decreased ATP and increased ROS production, enhanced apoptosis, activation of mTOR, altered autophagic flux, and an increased inflammatory response.⁸ Bellomo et al. demonstrated that the ketogenic diet reduced lysosomal cystine, decreased apoptosis, preserved autophagic flux, and inhibited kidney inflammation and fibrosis, altogether improving proximal tubular function and kidney morphology.⁵ Several complex mechanisms, reviewed by Zhu et al. and Rojas-Morales et al., could potentially contribute to this positive effect and warrant further study.^2,3 On one hand, the ketogenic diet directly stimulates mitochondrial ATP generation by offering an access of FAs, which are the preferred fuel of the proximal tubule .⁹ Circulating FAs enter proximal tubule cells through basolateral CD36, FABP, and FATP, subsequently crossing the mitochondrial membrane to undergo β-oxidation, which delivers acetyl-CoA to the TCA cycle, bypassing glycolysis. The kidney has also a significant capacity for ketone utilization in energy metabolism. BHB, one of the KB, is filtered by the glomeruli and reabsorbed by apical SMCT2. BHB, metabolized to acetoacetate (another KB) and subsequently to acetoacetyl CoA and acetyl-CoA, fuels the TCA cycle, directly boosting mitochondrial respiration. On the other hand, several lines of evidence indicate that BHB is an endogenous signaling molecule having antioxidant and anti-inflammatory properties.^2,3 BHB can reduce ROS production, increase cellular GSH, and enhance SOD1, thereby protecting cells against oxidative stress. BHB also enhances the antioxidant response by activating Foxo1, Foxo3, and NRF2, which increase the expression of antioxidant genes. Moreover, BHB activates mitochondrial SIRT3, a key regulator of mitochondrial function, enhancing FA oxidation and the TCA cycle, while inhibiting mitochondrial ROS production. Noteworthy, a previous study by Bellomo et al. demonstrated a downregulation of SIRT3 in the cystinosis proximal tubule.¹⁰ Furthermore, BHB has been shown to inhibit apoptosis, potentially increasing proximal tubule cell mass. BHB can also suppress the NLRP3 inflammasome, NF-kB, and STAT3, which are mechanisms that may reduce inflammation and fibrosis. In addition, BHB's inhibitory effect on mTOR can stimulate autophagy and activate TFEB, which promotes the expression of genes involved in lysosomal biogenesis, autophagy, lipid catabolism, energy metabolism, and exocytosis. TFEB activation can help reduce lysosomal cystine accumulation by enhancing lysosomal biogenesis and exocytosis. It is important to note that several of the mechanisms suggested and illustrated in the figure were observed in different model organisms and disease conditions and may not all be present in cystinosis mice fed a ketogenic diet. The figure's graphic design was created by Marcel Janssen from Ziehoe. AMPK, 5′ AMP-activated protein kinase; BHB, β-hydroxybutyrate; FA, fatty acid; FABP, fatty acid binding protein; FATP, fatty acid transport protein; Foxo1,3, forkhead box O protein 1 and 3; GSH, glutathione; KB, ketone bodies; MCT1, monocarboxylate transporter 1; mTOR, mammalian target of rapamycin; NLRP3, NOD-, LRR- and pyrin domain–containing protein 3 inflammasome; NRF2, NF erythroid 2–related factor 2; ROS, reactive oxygen species; SGLT2, sodium-glucose cotransporter 2; SIRT3, sirtuin 3; SMCT2, sodium-monocarboxylate transporter 2; SOD1, superoxide dismutase 1; STAT3, signal transducer and activator of transcription; TCA cycle, tricarboxylic acid cycle (also known as citric acid or Krebs cycle); TFEB, transcription factor EB.

The authors suggest several promising avenues for future research. One such direction involves the use of sodium-glucose cotransporter 2 inhibitors to further restrict glucose supply to the proximal tubule. However, given that patients with cystinosis typically exhibit pronounced glucosuria as part of Fanconi syndrome, it remains unclear whether the effects of sodium-glucose cotransporter 2 inhibitors without therapeutic ketosis would be beneficial. Another potential approach is the combined use of cysteamine and the ketogenic diet, which might enhance their mutual effects. In a clinical setting, the ketogenic diet's effect could only be assessed as an adjunct to cysteamine therapy, given cysteamine's proven efficacy in addressing both renal and extrarenal manifestations of cystinosis.

Interestingly, the ketogenic diet also seemed to have a positive effect on the elevated creatine phosphokinase levels indicative for myopathy observed in cystinosis mice—another promising area for future research.

As with all excellent studies, the work by Bellomo et al. work raises more questions than it answers. This pioneering study adds cystinosis to the growing list of diseases that may benefit from the ketogenic diet and warrants further investigation in both preclinical and clinical settings. In the meantime, caution is advised regarding the uncontrolled use of the ketogenic diet in patients with cystinosis because it could exacerbate metabolic acidosis due to ketosis and hypokalemia and hypophosphatemia because of the limited intake of vegetables and fruit, a potentially worsening feature of Fanconi syndrome. Moreover, the effects of the ketogenic diet in advanced CKD still need to be studied.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E850.

Funding

None.

Author Contributions

Conceptualization: Elena Levtchenko.

Writing–original draft: Fanny Oliveira Arcolino, Elena Levtchenko.

Writing–review & editing: Fanny Oliveira Arcolino, Elena Levtchenko.