Slowing Polycystic Kidney Disease by Fasting
Authors: Alessandra Boletta
Journal: Journal of the American Society of Nephrology (2015)

“We are what we eat.” This simple statement was originally set forth by the German philosopher L.A. Feuerbach (1804–1872) to express his belief that human beings have an empirical and physical nature that is as important if not more important than their spiritual and theological one. Over the past century, the same sentence has acquired a different meaning and has been used to underscore the effect of natural food and controlled eating on human health. While this cultural concept was being developed, a number of compelling observations have proven that calorie restriction has the power to extend the lifespan in all organisms ranging from yeast to mammals and primates, including human beings.2,3 Numerous studies have also shown that a lower calorie intake has a beneficial effect and reduces the risk of all-cause mortality, including malignancy, cardiovascular complications, and a number of chronic conditions.2 This is in addition to obesity and diabetes, which are known to be primarily metabolic disorders for which a reduction in food intake acts on the primary cause of disease.2,3 In a paper appearing in this issue of the JASN, Warner et al.1 show that FR can improve kidney disease in animal models of PKD. ADPKD is the leading genetic cause of ESRD, with an estimated prevalence of 1:500–1:1000.4 The disease is caused by inherited loss-of-function mutations in either the PKD1 or the PKD2 gene, encoding for Polycystin-1 and -2, mutated in 85% and 15% of patients, respectively. Although the disease is inherited as a dominant trait, the disorder is recessive at the molecular level. Somatic mutations can be identified in a substantial fraction of cyst–lining epithelial cells and are proposed to diminish the level of polycystin signaling below a critical threshold. This, in turn, results in the formation of focal, slowly proliferating, and fluid-filled cysts.4,5 Microdissection studies performed early in the course of ADPKD suggest that cystogenesis occurs in approximately 10% of nephrons.6 The relentless expansion of these cysts eventually causes compression and malfunction of all nephrons within the kidney, resulting in severe tissue damage accompanied by inflammatory infiltration and fibrosis. Many signaling pathways have been reported to be dysregulated in PKD kidneys, and there is recent evidence indicating that metabolic reprogramming plays a critical role in ADPKD kidneys.4,5,7–9 This has resulted in preclinical studies targeting metabolic pathways, such as glycolysis and the energy sensor AMP–activated protein kinase.7,8,10 Warner et al.1 now show that reducing food intake to levels that do not cause malnutrition (30%–50%) achieves an impressive improvement in the progression of PKD in animal models. Warner et al.1 use the Pkd1RC/RC hypomorphic murine model11 and compare the outcome in mice fed ad libitum with those who are subjected to a 40% FR from 6 weeks of age to 7.5 months of age. Warner et al.1 show that renal size is halved in animals on a calorie-restricted diet compared with ad libitum–fed animals.1 In addition, cystic index, inflammatory infiltrate, and fibrosis were also significantly decreased and reached levels comparable with those observed in age–matched wild–type animals. At a mechanistic level, Warner et al.1 show that hexokinase 2 (Hk2), but not other enzymes involved in glycolysis or the trichloroacetic acid cycle, is upregulated in Pkd1RC/RC and returns to baseline levels on FR.1 Although direct measures of metabolic alterations as well as measures of glucose consumption in Pkd1RC/RC mice in vivo await additional studies, the analysis of a cell line derived from the Pkd1del2/del2 animal model (different from Pkd1RC/RC) failed to identify glucose dependence. This is unexpected given the increase in Hk2 levels and indicates that additional investigation would be required to clarify the link between FR and Hk2 regulation. The study by Warner et al.1 further shows that FR likely acts through the liver kinase B1/AMP–activated protein kinase/mechanistic target of rapamycin complex 1 axis to improve disease progression. This is in line with the fact that metformin,10 rapamycin,12 and the calorie restriction mimetic 2-deoxy-d-glucose7 have all been shown to retard disease progression in a variety of PKD mouse models. Interestingly, Warner et al.1 show that FR has a therapeutic effect in mice with established cystic disease as well. In a second set of studies, Warner et al.1 tested the effect of calorie restriction initiated in older animals beginning at 5.5 months of age, when cystic disease is progressing. The authors1 report that a calorie-restricted diet started later in the disease course results in a similar improvement to the one observed by treating the animals before appearance of the cystic alterations. This suggests that FR has the potential to revert the cystic phenotype after it is initiated.1 Unfortunately, Warner et al.1 did not document by imaging the degree of cystic change in each animal before initiating FR at 5.5 months. This would have been critical to definitively prove that the treatment initiated at 5.5 months causes a true reversion of the cystic phenotype rather than simply delaying cyst development. Nevertheless, data on renal mass improvement after FR are impressive. Likewise, data correlating the degree of FR (10%, 20%, 30%, or 40%) with renal size improvement1 open the way to novel treatments. Indeed, a minimal food (or calorie) restriction, easily tolerable in humans, might provide a reasonable therapeutic strategy. One possible obstacle in translating FR directly to humans is the issue of patient compliance with calorie restriction.13 Indeed, despite the vast preclinical literature highlighting the potential benefit of calorie restriction, adherence to such interventions has been a challenge, even in conditions such as obesity and diabetes, where the benefits are quite clear.13 For this reason, much effort has been made toward the identification of molecules (drugs) that could mimic a reduction in calorie intake, the so–called calorie restriction mimetics, with some good candidates having been identified.14 While awaiting for the miraculous pill, an exciting study recently described the beneficial effects of a new diet mimicking intermittent fasting.15 Brandhorst et al.15 showed that, in yeast, cycles of fasting followed by refeeding can also extend lifespan. Furthermore, the bimonthly administration of a diet that mimics the effects of intermittent fasting extended the median lifespan of mice (not their absolute lifespan), reduced cancer incidence, and rejuvenated the immune system. Importantly, Brandhorst et al.15 also performed a small randomized pilot clinical trial and showed that a fast-mimicking diet recapitulated, at least in part, the effect of intermittent fasting for several parameters in humans as well. Thus, diets ensuring intermittent calorie restriction might ultimately provide a reasonable therapy for a number of diseases, including ADPKD. Overall, the work by Warner et al.1 in this issue of the JASN has several important implications: (1) it builds on previous knowledge and underlines the importance of the kidney metabolic rate in the progression of PKD; (2) it shows, for the first time, that simple changes in the diet might halt disease progression in PKD; and (3) it provides novel hints of strategies that might retard and revert cyst expansion. The murine models used in this study carry either Pkd1 hypomorphic mutations in homozygosity (the Pkd1RC/RC model) or a hypermutable Pkd2 allele (Pkd2SW25). These are both considered mild forms of the disease in humans.16 In future studies, it will be essential to test whether this treatment is also beneficial in other PKD animal models carrying truncating Pkd1 mutations, because these are the types of mutations that result in the most severe disease manifestations.16 This will be critical in identifying suitable therapeutic strategies that are broadly applicable to all patients with ADPKD. Disclosures A.B. is a coinventor on a patent for the inhibition of glycolysis and the use of 2-deoxy-d-glucose in PKD. A.B. has been on Advisory Boards for Otsuka Pharmaceuticals Europe Ltd., Wexham, UK in the past 2 years.