Ketogenic diet can be used to treat polycystic kidney disease

Hereditary and relatively common, polycystic kidney disease (PKD) has long been thought to be progressive and irreversible, condemning its sufferers to a long, slow and often painful decline as fluid filled cysts develop in the kidneys, grow and eventually rob the organs of their function.

Once their kidneys fail, PKD patients often require dialysis several times a week or must undergo a kidney transplant.

To make matters worse, a host of other PKD-related conditions and complications add to the patients’ health burden, including high blood pressure, vascular problems and cysts in the liver. And that doesn’t take into account the medical costs and the reduced quality of life.

Progress toward finding a cure has been sluggish, with only one drug proven to slow—but not stop—the progression of PKD.

But now, thanks to research conducted by UC Santa Barbara biochemist Thomas Weimbs, postdoctoral researcher Jacob Torres and their team, a solution may be no farther than the end of your fork. Diet, they discovered, could hold the key to treating PKD.

“It’s surprisingly effective – much more effective than any drug treatment that we’ve tested,” Weimbs, whose work focuses primarily on the molecular mechanisms underlying polycystic kidney disease and related renal diseases, said of his group’s discovery. Their work appears in the journal Cell Metabolism.

A fast(ing) response

In previous studies, the research team found that reducing food intake in mouse models slowed the growth of polycystic kidneys; but at the time, they did not know why. In their new paper, the scientists have identified the specific metabolic process responsible for slowing the progress of the disease.

The best part? It’s a process many of us already know well.

“There’s a way of avoiding the development of the cysts through dietary interventions that lead to ketosis,” Weimbs said.

You heard that right: Ketosis, the underlying metabolic state of popular diets such as the ketogenic diet, and, to a lesser extent, time-restricted feeding (a form of intermittent fasting), has been shown in the Weimbs group’s studies to stall and even reverse PKD.

“The cysts appear to be largely glucose-dependent,” Weimbs explained. In people with the predisposition toward PKD, the continuous supply of sugar in the high-carbohydrate, high-sugar diets of modern culture serve to feed the growth and development of the fluid-filled sacs.

“Ketosis is a natural response to fasting,” Weimbs said. “When we fast, our carbohydrate reserves are very quickly used up.

In order to not die, our bodies switch over to a different energy source and that comes from our fat reserves.”

The fat reserves, he continued, are broken down into fatty acids and ketones which then take the place of glucose in providing energy to the body.

The Weimbs team found that the presence of ketones in the blood stream in particular inhibits the growth of the kidney cysts. And with a steady supply, ketones actually acted to reverse the condition in their animal studies.

The problem with typical Western diets is that we almost never go into ketosis: we eat high-carb, high-sugar foods almost continuously throughout the day, securing for ourselves a continuous supply of glucose.

In the ketogenic diet, the body’s typical “go-to” source of energy – glucose – is taken away as ketogenic dieters focus on non-carbohydrate foods, eventually forcing their bodies to mimic the fasting response.

Time-restricted feeders, meanwhile, reach that state by limiting the window of time they eat to a small part of the day, leaving the remaining 16-20 hours of their day for the body to use up the carbs and sugars and switch over into ketosis.

Ketones are actually a class of three different naturally occurring molecules, said Weimbs. Of particular interest and effectiveness is one called BHB (beta hydroxybutyrate), which has been shown “to affect numerous signaling pathways that are implicated in PKD,” according to the study.

The team found that by just feeding that ketone to rats with PKD, they were able to create the beneficial effects of ketosis, no special diet restriction needed.

“Which makes this really amazing,” Weimbs said.

“On top of a normal high-carb diet, which they can eat all day long, if we give them BHB, they’re fine.” After five weeks of treatment with BHB in the drinking water, rat polycystic kidneys were “nearly indistinguishable” from normal ones.

In fact the researchers were so surprised by their result they thought they had made a mistake.

“I was so surprised by the effect of BHB treatment that I had to go and double-check all the genotypes of the animals to make sure they had PKD to start with,” said Torres, the paper’s lead author.

“The effect was really unlike anything I had encountered before.

“The impact of this research has huge implications on the field of PKD,” Torres continued. It provides a framework, he said, for understanding the pathology of PKD from a metabolic viewpoint and adds another disease to the list that a ketogenic diet can be used to treat.

“Our discovery also has implications for understanding cellular metabolism at a fundamental level as we learn more about what has gone wrong in our disease models. I am really looking forward to the future of research in this field as we explore this new space and uncover even more about what is really going on in PKD.”

An assist with ketosis

It’s quite possible to reach ketosis just by avoiding carbs or by fasting for a period of time. “It’s a very natural way to have your own body produce BHB,” Weimbs said. “So something like a time-restricted diet is feasible.”

But the key to success with diet-related issues is consistency. Ask virtually any dieter and they’ll tell you that staying on track is the difficult part.

For those with polycystic kidneys who could use an assist with ketosis, whether or not they need to lose weight or wish to change their diets, the Weimbs lab is developing a dietary supplement to add BHB to their regular intake.

This patent-pending nutritional supplement would be similar to commercially available ketone products being offered as energy boosters, but formulated specifically for supporting kidney health.

“We want to make sure we don’t put anything harmful into the bodies of people with potentially compromised kidney function,” Weimbs said. “And some of the ketone products already out there are high in potassium and other ingredients that could be detrimental.”

In addition, the supplement being developed is combined with another nutrient the Weimbs Lab has recently shown to inhibit cyst formation in PKD by a completely different mechanism from BHB, thereby approaching the problem from two directions.

While not a drug – and therefore less expensive and essentially free of serious side effects – the supplement is nevertheless intended for use by those under medical supervision. Members of the Weimbs team are planning to conduct a clinical trial to test their supplement mixture in people with PKD.

Assuming all goes well, they are planning to launch a company to make it available.

“We’re really excited that we can actually provide a supplement that potentially could help many more people than dietary intervention alone,” Weimbs said.

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Autosomal-dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of end-stage renal disease in adults. Affected individuals and families face a significant medical and psychosocial burden due to both renal and extrarenal manifestations.

Consequently, interventions that ameliorate the course of the disease and specifically slow down the loss of kidney function are of special interest. Major research efforts in both the clinical and pre-clinical setting in the last two decades resulted in a number of pivotal clinical trials aimed to ameliorate the disease.

These studies have underlined the important role of specific supportive measures and provided the basis for first targeted pharmacological therapies. Very recently, the concept of repurposing drugs approved for other conditions for a use in ADPKD has gained increasing attention.

Here, we review the current best-practice management of ADPKD patients with a focus on interventions that have reached clinical use to maintain kidney function and give an outlook on future trials and potential novel treatment strategies.

INTRODUCTION

Cystic kidney diseases are caused by mutations in genes encoding proteins that are important for the function of primary cilia – a fact that led to the classification of these diseases as ciliopathies [1, 2].

Defective biogenesis or impaired function of primary cilia impacts proliferation, cell survival, polarity and secretion of renal epithelial cells [3]. These cell biological phenotypes are then the basis of cyst formation and progressive loss of kidney function.

In the clinical setting, cystic kidney diseases can be separated into several groups of disorders based on age of onset, kidney morphology and extrarenal findings [4, 5].

Primarily, disorders of the nephronophthisis spectrum are distinguished from autosomal-recessive and autosomal-dominant polycystic kidney disease (ADPKD). Furthermore, there is also a significant phenotype–genotype overlap with other entities such as HNF1ß-associated nephropathy [6], autosomal-dominant tubulointerstitial kidney disease [7] and familial tumour syndromes (namely tuberous sclerosis, von-Hippel-Lindau, Birt-Hogg-Dubé and renal coloboma syndromes) [4].

Differential diagnosis of cystic kidney diseases relies primarily on clinical criteria based on kidney morphology and specific extrarenal findings. ADPKD is characterized by bilateral large kidneys showing a distribution of cysts throughout the entire parenchyma (Figure 1).

The disorder may cause flank pain, cyst haemorrhage, nephrolithiasis and progressive loss of kidney function. However, cysts do also occur in other organs (e.g. liver, pancreas, spleen).

Moreover, additional extrarenal complications may be observed in ADPKD patients including intracranial aneurysms (ICA), biliary tract disease, intestinal diverticulosis and cardiac valve defects [8, 9] (Figure 1).

Primarily, two genes are involved in the pathogenesis of ADPKD—PKD1 and PKD2. Other genes have been implicated in cases in which no mutation could be detected; however, these novel genes (DNAJB11, GANAB) play a minor role taking into account the low frequency in ADPKD patients [10].

Importantly, truncating PKD1 mutations leads—on average—to end-stage renal disease (ESRD) ∼20 years earlier than PKD2 mutations [11]. Molecular genetics are rarely needed for making a diagnosis in ADPKD patients with a positive family history based on clear imaging criteria [12].

However, the genetic lesion may play a more prominent role in the future to predict the course of the disease and allow for counselling regarding therapeutic options [13].

Furthermore, a molecular genetic diagnosis should be obtained if the clinical presentation does not allow for a clear diagnosis and in cases in which one of the tumour syndromes is suspected to allow for early prognostic testing of other family members [4].

In the past, the only therapeutic options available were supportive measures largely extrapolated from other chronic kidney diseases (CKDs) (Table 1).

This has changed tremendously in the last years. On one hand, general interventions such as blood pressure control have been emphasized in ADPKD by randomized trials [14].

On the other hand, the Tolvaptan Phase 3 Efficacy and Safety Study in ADPKD (TEMPO) 3:4 trial has led to the approval of the first targeted therapy for this disease with tolvaptan having been approved for the treatment of ADPKD patients in Europe, Canada, Japan and recently in the USA [15].

Here, based on these new advances, we are summarizing the current state-of-the art in managing ADPKD with a focus on measures alleviating estimated glomerular filtration rate (eGFR) loss.

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More information: Jacob A. Torres et al. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease, Cell Metabolism (2019). DOI: 10.1016/j.cmet.2019.09.012

Journal information: Cell Metabolism
Provided by University of California