Intermittent Fasting, Inflammation, and PKD

Have you been watching the incredible research and progress with diet and PKD? Well, let me fill you in.

When it comes to preserving kidney function, a plant based diet is the primary approach we start with for most of our clients. But a 100% plant-based diet isn't right for everyone.

Polycystic kidney disease is one area where targeting a slightly different approach that incorporates intermittent fasting or a carefully managed ketogenic diet may have some benefits in shrinking cyst growth

This is a big topic, but we wanted to cover briefly some of the thoughts and research behind PKD and intermittent fasting as it could be a viable dietary option.

This post may be a little bit heavy on the medical lingo and jargon, for which we apologize ahead of time. We're working on a simplified version but thought this may still be useful for some people or practitioners.

Intermittent fasting and PKD

The introduction of and implementation behind intermittent fasting (IF) is a dietary approach that addresses less WHAT you eat, and more WHEN you eat. We of course, still believe in the WHAT, but for some people targeting WHEN can have extra benefits.

Extended periods of fasting have proven to provide metabolic benefits for several chronic conditions, including metabolic syndrome, diabetes mellitus, cardiovascular disease, cancer, and rheumatoid arthritis, through the repair of cellular damage.¹

The concept of resting and resetting cells during periods in which you don't consume any calories (not eating OR drinking) occurs has been deemed the “fasting physiology” – a theory which is currently being employed to explain the imperative restoration and rejuvenation mechanisms that occur during only the fasting stage.

Fasting physiology actions have been shown to be elicited sooner and for longer periods of time when the body is in a caloric restriction, or on a consistent time-restricted feeding regimen, through a mechanism in which Tor-S6K signaling is inhibited, thereby activating autophagy.²

A promising study that Sutton et al. conducted was the first controlled feeding trial which demonstrated promising improvements of insulin sensitivity, blood pressure and oxidative stress, in participants which did not require weight loss. This helped to validate the benefits of IF and cardiometabolic health beyond those benefits of weight loss itself.³

Outside of weight loss, intermittent fasting has also been used reliably in the treatment of several inflammatory diseases, such as rheumatoid arthritis, diabetes mellitus, multiple sclerosis, and IBD. These benefits have been observed through the use of several different styles of intermittent fasting, with advantages and disadvantages noted in each case.

There are four different approaches to intermittent fasting commonly used:

Table 1. Comparison of IF Restrictions (1)

TYPES OF FASTING

Alternative Day Fasting

Alternate-day fasting includes alterations of two full fasting days, with the consumption of zero calories, and five feeding days comprised of ad libitum consumption of foods and beverages. This method has proved an effective means for a reduction in body weight through simple caloric restriction and was accompanied by benefits for glucose response, reductions in both fasting insulin and glucose concentrations, as well as reductions in lipid profiles of total plasma cholesterol, triglyceride concentration, liver steatosis.¹

Additionally, there was a reduction in inflammatory gene expression which in turn helps to reduce cell proliferation and decrease the risk of multiple cancer factors.

However, this method had the greatest documented shortcomings comprised mostly around reports of extreme hunger which led to distraction and decreased productivity throughout the day, as some participants found themselves constantly thinking about food. Due to those reasons, this may make this a less than ideal public health intervention for many individuals.¹

Modified Fasting Regimen

Modified fasting regimen, also known as intermittent energy restriction, limits the amount of energy consumed to 20-25% of the regular intake rather than completely eliminating energy intake all together on the fasting days. The two days of fasting should still be nonconsecutive and the other five days of the week maintain unrestricted energy consumption.

In animal studies, the comparison of ad libitum energy consumption to this fasting regimen demonstrated decreased visceral fat, leptin, and resistin, with an increase in adiponectin.¹

In humans, this method demonstrated a decrease in fasting insulin as well as fasting glucose, with improvements of inflammatory markers such as CRP, tumor necrosis factor-α (TNF-α), adiponectin, leptin, and brain-derived neurotrophic factor (BDNF). Participants reported an increase in feelings of fullness to accompany the laboratory findings of elevated peptide tyrosine tyrosine (PYY), indicating that there was indeed a change in ghrelin and/or other gut peptides related to feelings of hunger and fullness.

When compared to continuous energy restriction, this method did not present any additional benefits, but it may serve some individuals personal preferences and lifestyle requirements better.¹

The Fasting-Mimicking Diet

The Fasting-Mimicking Diet (FMD) is based around a diet comprise of low protein and low sugar, with relatively high unsaturated fat. This diet was developed to address the negative consequences associated with the rapid weight loss observed on a water only fast. In animal models, this diet resulted in a reduction of neoplasms and inflammation as well as an improvement in behavioral tests.³

Time-restricted eating offers the most variability in its fasting intervals, with anywhere from 12-21 hours of fasting time.¹ There are several variations of windows which can be implemented, in order from greatest time restriction to least. Typic typical patterns include 21 hrs fast with 3 eating (21:3);, 20 hours fasting with 4 hours eating (20:4); 18 hours fast with 6 hours eating (18:6), 16 hours fasting, 8 hours eating (16:8), 14 hr fast with 10 hours for eating (14:10), and 12 hours fasting with 12 hours eating (12:12).

The most commonly researched implementation is that of the 16:8 fasting pattern, but many individuals have found that when this is too restrictive. The 12:12 or 14:10 offers the flexibility necessary to maintain this lifestyle.

Consistent benefits have been observed when consuming foods earlier in the day, no matter which fasting window is utilized, and ensuring that the last energy consumption occurring before 8 pm. In animal models, all of these fasting windows resulted in reduction in body-weight, insulin resistance, total cholesterol, TGs, glucose, insulin, interleukin 6 (IL-6) and TNF-α.¹

Timing

Interestingly, a study conducted about the omission of breakfast, found that participants had higher levels of acetylated ghrelin prior to eating as well as higher post-lunch postprandial glucose and insulin levels accompanying lower postprandial PYY, leptin, and acetylated ghrelin without a change in appetite later in the day – yet, there were no benefits specifically observed on weight change, glycemic control, lipids, or inflammatory markers for participants who omitted breakfast.¹

On the contrary, most of the research looking into the timing of the non-fasting window has indicated that breaking the fast earlier in the day accompanied with an earlier return to fast, has significant metabolic benefits including an increased rate of uptake and utilization of glucose for energy, whereas the energy consumed later in the evening is typically converted into fat for storage.

Dr. Satchidanana Panda has conducted countless research studies on the area of time restricted eating, both in humans and in mice, in order to understand the role that timing of meals has on the circadian rhythm.⁵

The circadian rhythm in turn mediates the body’s immune system and thereby, the activation of inflammatory response molecules. Dr. Panda’s research found that higher levels of inflammation were observed when energy consumption occurs later in the day – specifically, in the hours after daylight. In the midst of the research on timing of energy consumption and the body’s inflammatory response, Dr. Panda’s team discovered a blue-light sensitive protein called melanopsin, which also helps to regulate our circadian clock, sleep and alertness.^5,6

In a human pilot study with metabolic syndrome participants, Dr. Panda also found that when the dietary intake was reduced to just a 10-hour window with the last meal consumed before 8:00pm, participants’ cardiometabolic health improved significantly to exhibit reduced waist circumference, body fat, visceral fat, blood pressure, atherogenic lipids, and glycated hemoglobin.

This suggests that health benefits observed from time restricted eating may not have as much to do with the variation of feeding hours, such as 12:12 versus 14:10, but more so the consistency of meal times and the avoidance of nighttime feeding.⁷

Part of the explanation for these metabolic profile improvements may also lie in the natural functions of gastrointestinal microbiota as they align with the circadian rhythms to provide increased gastric emptying and blood flow during daytime rather than at night.

The gastrointestinal tract maintains a heightened metabolic response to glucose loads earlier in the day, which can explain the benefits observed with refrainment from nighttime feeding. During feeding, insulin-pAKT-mTOR pathways drives anabolic processes while fasting allows for AMPK to be activated in order to initiate repair and catabolic processes.²

Fasting has also shown to allow for repair of damaged cells - in conditions such as leaky gut, this provides an opportunity for the gut permeability to be reduced, thereby blunting postprandial endotoxemia and systemic inflammation.¹

Studies from the Salk Institute for Biological Studies even found that the brain-gut pathway is activated during fasting to further promote energy balance. ¹ This circadian rhythm regulation of behaviors, hormones, physiology, metabolism, and energy is demonstrated in figure 2 which was obtained from reference 1.

Intermittent fasting and kidney disease

Warner, et al. found that a food restriction of 30-50% can employ the same metabolic sensors - AMPK, mTOR-S6K, and SIRT1 – as those which impact the progression of ADPKD and may thereby offer a means of slowing disease progression. ⁸

Their research on animal models included a 40% food restriction over 6 months to determine the metabolic effects on ADPKD progression – their results found that these metabolic adaptations almost completely inhibited the development of renal cysts while providing a significant reduction in the ratio of the size of the kidney to the unchanging size of the heart. This research demonstrated that food restriction can inhibit cytogenesis in Pkd1^RC/RC animal models as well as decrease renal inflammation, fibrosis, and markers of injury.⁸

Additionally, the expression of proliferating cell nuclear antigen (PCNA), which serves as a marker of cellular proliferation, and caspase-3, a marker of apoptosis, were both significantly decreased. When Warner, et al. introduced food restrictionas a therapeutic diet in older animal models which exhibited a heighten disease state, the results revealed improvements parallel to those in animals treated prior to the development of cysts.⁸

While food restriction has successfully been shown to benefit PKD symptoms in animals’ studies, it is believed that the slowed progression is actually due to the induction of ketosis through TRF, as TRF without food restriction inhibited mTOR signaling, proliferation, and fibrosis in the kidneys.

Three methods were compared by which the models were shifted into a state of ketone utilization, all of which demonstrated the above metabolic benefits: 1) the ketogenic diet, 2) time restricted eating, and 3) an exogenous oral administration of exogenous ketone β-hydroxybutyrate (BHB).

In addition, the ketogenic diet provided additional regression of renal cystic burden, the acutely fasted animal PKD models demonstrated a rapid reduction of cyst volume, and the administration of exogenous BHB showed inhibited progression of ADPKD in the animal models.⁹ If this research were to translate successfully to human models, it would show opportunity for inhibited and possible reversal of cyst formation through either the ketogenic diet, ketosis induced via intermittient fasting, or BHB supplementation. 

Dr. Kristen L Nowak and Beverly Farmer at the University of Colorado, Denver have designed a study to determine the effects of Daily Caloric Restriction and Intermittent Fasting in Overweight and Obese Adults with Autosomal Dominant Polycystic Kidney Disease. This is a 12-month randomized, double blind clinical trial implemented in 28 patients with an ADPKD diagnosis and a BMI of 27-45 kg/m².

The study’s primary completion date is set for September 1, 2020 and should be followed up with to review the results of intermittent fasting in human models.¹⁰ Nowak’s previous publications attributed the defective glucose metabolism, dysregulated lipid and amino acid metabolism, impaired autophagy and mitochondrial dysfunction to the high metabolic demand placed on the kidneys which lead to cystic proliferation and growth.¹¹

The research on intermittent fasting is continuously growing for a number of chronic diseases, especially those which are inflammatory driven, and may soon provide a means of medical nutrition therapy for new conditions which were unsuccessfully addressed in the past.

There is promising research being conducted in attempts to uncover possible treatment options using intermittent fasting for genetic conditions such as ADPKD. At this time, there have been no major side effects revealed as a consequence of this dietary lifestyle, however, it may not be a one size fits all.

Different lifestyles, work requirements and personal preferences should be taken into consideration when deliberating which, if any, intermittent fasting method should be commissioned.

Conclusion

So if you're looking at preserving kidney function with polycystic kidney disease should you consider intermittent fasting? Yes it is definitely something we believe can be helpful. However, it is not a "magic bullet" solution for everyone with PKD if other things are not taken into consideration. Kidney disease has many components to it that play into progression and stabilization. Sodium, iron, oxalates, are just 3 of many that should be looked at.

Our team at the Kidney Nutrition Institute and RISE Nutrition for PKD is excited about being a leader in developing and utilizing therapies like intermittent fasting and keto diets for people with PKD to preserve their kidney function.

If you are interested in working with one of our expert renal dietitians, please reach out to us to schedule a complimentary RISE nutrition strategy call.

Author: Libbi Loos, RD and Jessianna Saville, MS, RDN, CSR, LD

References:

1. Patterson RE, Sears DD. Metabolic Effects of Intermittent Fasting. Annual Review of Nutrition. 2017;37(1):371-393. doi:10.1146/annurev-nutr-071816-064634.
2. Longo VD, Panda S. Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab. 2016;23(6):1048–1059. doi:10.1016/j.cmet.2016.06.001
3. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell metabolism. https://www.ncbi.nlm.nih.gov/pubmed/29754952. Published June 5, 2018. Accessed February 28, 2020.
4. Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai8700. doi:10.1126/scitranslmed.aai8700
5. Satchidananda Panda. Salk Institute for Biological Studies. https://www.salk.edu/scientist/satchidananda-panda/. Accessed March 1, 2020.
6. Hatori M, Gronfier C, Van Gelder RN, et al. Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies. NPJ Aging Mech Dis. 2017;3:9. Published 2017 Jun 16. doi:10.1038/s41514-017-0010-2
7. Wilkinson MJ, Manoogian ENC, Zadourian A, et al. Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome. Cell metabolism. https://www.ncbi.nlm.nih.gov/pubmed/31813824. Published January 7, 2020. Accessed March 1, 2020.
8. Warner G, Hein KZ, Nin V, et al. Food Restriction Ameliorates the Development of Polycystic Kidney Disease. American Society of Nephrology. https://pubmed.ncbi.nlm.nih.gov/31631001/. Published May 1, 2016. Accessed February 27, 2020.
9. Torres JA, Kruger SL, Broderick C, et al. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/pubmed/?term=Ketosis+Ameliorates+Renal+Cyst+Growth+in+Polycystic+Kidney+Disease. Published October 17, 2019. Accessed March 1, 2020.
10. Daily Caloric Restriction and Intermittent Fasting in Overweight and Obese Adults With Autosomal Dominant Polycystic Kidney Disease - Full Text View. Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03342742. Published November 17, 2017. Accessed February 27, 2020.
11. Nowak KL, Hopp K. Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Evidence and Therapeutic Potential. Clinical journal of the American Society of Nephrology : CJASN. https://www.ncbi.nlm.nih.gov/pubmed/32086281. Published February 21, 2020. Accessed February 28, 2020.