The ketogenic diet, characterized by high-fat, moderate-protein, and very low-carbohydrate intake, has gained popularity as a weight loss strategy and potential therapy for various conditions. This dietary approach forces the body to switch its primary fuel source from glucose to ketones, entering a metabolic state known as ketosis. While the ketogenic diet has shown promise in certain areas, its impact on kidney health, particularly in individuals with kidney disease, remains a subject of ongoing research and debate.
Understanding the Ketogenic Diet
The ketogenic diet typically consists of 60-80% of calories from fat, 15-20% from protein, and only 5-10% from carbohydrates, often limiting carbohydrate intake to 20-50 grams per day. This drastic reduction in carbohydrates leads to decreased insulin secretion and depletion of glycogen stores, prompting the body to produce ketones from fat breakdown. These ketones, including acetoacetate, acetone, and beta-hydroxybutyrate (BHB), become the body's primary energy source.
The term "ketogenic diet" was coined in 1921 by Russell Wilder, who initially used it to treat epilepsy. While it gained traction for pediatric epilepsy treatment, its popularity waned with the advent of antiepileptic drugs. However, the ketogenic diet has experienced a resurgence in recent years, primarily for weight loss and management of other health conditions.
Potential Benefits of Ketogenic Diet
Some proven advantages to the keto diet have been reported in the literature. The most common clinical use of the keto diet is for refractory epilepsy in children. Hormones that are released and suppressed during fasting and eating are also involved in the initiation and suppression of seizure activities. One study also showed the benefit of ketosis in decreasing the cysts in polycystic kidney disease. The study suggested that the activity of the mTOR molecule activated in polycystic kidney disease is highly dependent on the presence of glucose.
Potential Risks and Concerns for Kidney Health
Despite its potential benefits, the ketogenic diet raises concerns regarding kidney health, especially for individuals with pre-existing kidney conditions. Renal dysfunction associated with the ketogenic diet has been reported in individuals with underlying kidney disease exposed to high protein. The diet's most common and easily reversible consequences are constipation, low-grade acidosis, hypoglycemia, kidney stones, and increased lipid in the blood. Increased acid production from a ketogenic diet may cause metabolic acidosis and related issues, including weakened bone health.
Read also: Managing Stage 3 Kidney Disease with Diet
High Protein Intake
A common concern is the potentially high protein intake associated with some ketogenic diets. While there is no universal definition of a high-protein diet, intakes exceeding 1.5 grams of protein per kilogram of ideal body weight are generally considered high. The average required protein intake for individuals with ideal body weight is 0.6 grams per kilogram. High protein intake has been shown to directly cause an increase in kidney volume and weight in a mouse model, resulting in the expansion of the mesangial matrix and tubulointerstitial fibrosis.
The proposed mechanisms of high protein dietary intake for kidney damage include mediators including acid load, high phosphate content, gut microbiome dysbiosis, and inflammation. In experimental rat studies, it has been suggested that increasing the protein dose increased the expression of proinflammatory genes.
A diet high in protein can cause intraglomerular hypertension, leading to glomerular hyperfiltration, injury, and proteinuria. One of the largest human trials showed that a high protein diet increased estimated glomerular filtration (eGFR) by 3.8 ml/min after six weeks compared with a lower protein diet. This leads to hyperfiltration and proteinuria in the early stages but eventually results in loss of kidney function.
Kidney Stones
Additionally, it is known that consuming animal protein leads to a higher incidence of kidney stones. Studies have shown that the source of the dietary protein also matters; it is noted that animal protein has a higher incidence of kidney injury compared to plant-based protein.
Acute Kidney Injury
Few cases exist in the literature regarding the keto diet causing acute kidney injury. One case study reported a 36-year-old female patient presenting with acute kidney injury induced by a ketogenic diet. She had no history of hypertension, diabetes, or kidney disease in the past.
Read also: A Review of the Mediterranean Diet in Kidney Disease
Ketogenic Metabolic Therapy (KMT) and CKD
Ketogenic metabolic therapy (KMT) is a medical nutrition therapy to address certain health and disease conditions. It is increasingly used for many non-communicable diseases that are rooted in abnormal metabolic health. Since chronic kidney disease (CKD) is commonly caused by overnutrition leading to hyperglycemia, insulin resistance and diabetes mellitus, the carbohydrate restriction inherent in KMT may offer a therapeutic option.
Numerous studies have found that various forms of KMT are safe for individuals with CKD and may lead to improvement of renal function. This is in contrast to the current standard pharmacological approach to CKD that only slows the relentless progression towards renal failure.
The term ‘ketogenic metabolic therapy’ (KMT) instead of ‘ketogenic diet’ is used to make it clear that a form of medical nutrition therapy (MNT) is being discussed to address certain health conditions related to chronic kidney disease (CKD), in contrast to ‘diet’ or culinary preferences. There are different ways of implementing KMT, but the common feature is the goal of switching the body's metabolism to a state of ketosis.
Ketosis induced by fasting is a form of KMT. However, continuous fasting can, naturally, not be a long-term solution for an MNT. This led to the development of ketogenic diets >150 years ago that substantially restrict carbohydrates, e.g. ≈20-50 g/day (as opposed to 100->300 g/day in most societies).
In addition to inducing fat weight loss, KMT may also have anti-inflammatory effects that appear to be largely due to the ketone BHB. BHB is not only an energy carrier, but is also a potent signaling molecule that activates its receptor, the G protein-coupled receptor GPR109a, at blood levels that occur during ketosis.
Read also: Nutrition and stage 2 CKD
Addressing Misconceptions about KMT
Nephrology professionals also tend to approach ketogenic diets with caution due to the perception of them either being high in protein and driving kidney decline or exacerbating cardiovascular risk due to high red meat and animal fat intake. These assumptions may be incorrect.
Medical professionals commonly confuse ‘ketosis’ with ‘ketoacidosis’. However, besides the fact that they rhyme, they have nothing in common. Ketosis is a normal physiological metabolic state, characterized by low blood glucose levels and moderate blood ketone levels. In contrast, ketoacidosis occurs primarily in type 1 diabetes mellitus, is characterized by extremely high blood levels of both glucose and ketones and is a serious pathologic condition.
A common misconception is the incorrect belief that carbohydrates, also commonly abbreviated as carbs, are essential nutrients. As known in biochemistry, they are not. The human body can synthesize all needed carbohydrates. Humans are able to adapt to low carbohydrate intake.
Another common misconception is that ketogenic diets must be high protein diets or even animal-based diets. This is incorrect. The only requirement is that carbohydrate intake is restricted sufficiently and that triglyceride intake is correspondingly increased. However, plant-dominant (PLADO) and plant-focused ketogenic diets have been used increasingly in recent years, and KMT can be well consistent with the use of PLADO low protein diets and plant-focused nutrition in diabetic kidney disease (PLAFOND) diet regimens.
Some investigators think that ‘high fat Western’ diets are the same as ketogenic diets. High fat Western diets are frequently used in animal experimentation, where they wreak havoc on the metabolism of rodents , but these diets invariably also have a high carbohydrate content that prevents the state of ketosis.
Rationale for Using KMT in CKD
A quintessential rationale is the premise that diabetes is by far the leading cause of CKD. Whereas the exact mechanisms may still be opaque, chronic hyperglycemia has direct effects on the kidneys, eventually causing vascular and tubular damage, chronic inflammation and fibrosis. If hyperglycemia triggers CKD, it is a logical conclusion that hyperglycemia should be ameliorated as much as possible to prevent further renal health deterioration.
KMT is an effective method of decreasing baseline blood glucose levels and reducing spikes. Numerous studies suggest that ketogenic diets are more effective in glycemic control, weight loss and decreasing hypertension than low fat diets.
In contrast, ketogenic metabolic therapy (KMT) reverses these underlying factors. The restriction of carbohydrate intake in KMT leads to normoglycemia and prevents glucose spikes, lowers insulin levels and reverses insulin-resistance and hypertension.
Chronic inflammation is a common feature of all forms of CKD and a major contributor to fibrosis and renal decline. Current nephrology guidelines do not contain KMT-based approaches and hence clinicians may be reluctant to use them in practice due to the incorrect assumption that considering KMT is a deviation from guidelines.
Evidence from Human Studies
Beyond animal studies, there are several human studies reporting on the safety, feasibility and efficacy of KMT in CKD. In general, KMT proved safe and feasible (relatively high adherence) and improved renal function in these studies. Because protein restriction has traditionally been central to most dietary guidelines for CKD management, it is important to note that many of these studies used a higher protein approach along with ketosis and still saw benefits.
A randomized controlled trial comparing a 2-year intervention with a ketogenic (low carbohydrate, high fat/protein) diet versus a Mediterranean diet versus a conventional low fat diet in 322 overweight or obese participants with mild-moderate CKD (stages 1-3) showed that the dietary interventions led to weight loss and improved renal function.
Ketogenic Diets for Weight Loss
In nephrology, two main applications of ketogenic diet are currently identified: weight loss, with different objectives according to the stage of chronic kidney disease (CKD), namely in the early stages of CKD to stabilize kidney function and control proteinuria, in the late stages of CKD mainly to allow access to kidney transplantation, and, more recently, the treatment of autosomal dominant polycystic kidney disease (ADPKD), the latter being a matter of some concern in our field .
In general, to be defined as ‘ketogenic’, the diet must not exceed 30-50 g of carbohydrate per day. Ketogenic diets induce a condition called “nutritional ketosis”. Nutritional ketosis is characterized by a blood ketone level between 0.5 and 3 mg/dl. However, it has been reported that to obtain a therapeutic effect, the ketone concentration should ideally be higher, between 5 and 8 mg/dl: this is called “therapeutic ketosis”. The therapeutic effect is mediated by several mechanisms, including reduction in blood glucose, glycated hemoglobin and serum insulin levels, improvement in insulin sensitivity, reduction in hunger and reduction in inflammation .
Ketogenic Diet and Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Keto diets are a hot topic in the PKD community. Many people with PKD are keen to do all they can to slow kidney damage and stay healthy, including following a healthy diet and lifestyle. There is some scientific evidence from animal studies that keto diets might help to protect ADPKD kidneys. In mice with PKD, reducing food intake slowed the progression of the disease (e.g., slowed cyst growth). Researchers have found that some cells lining some kidney cysts die back in mice on keto diets, causing those cysts to shrink.
A recent small study in Germany compared a ketogenic diet (23 people) to a normal diet (19 people) in people with ADPKD. Over this time, the average size of people’s kidneys in the control group increased but in the ketogenic diet group decreased. While this is promising, the number of people in the study is small, and the results did not hold up to statistical analysis. Of concern, the study found signs that the ketogenic diet trialled might not be safe for everyone. Two people on the ketogenic diet got kidney stones. Also, more people on the ketogenic diet than normal diet got slightly increased levels of fats called triglycerides and cholesterol in their blood.
Another study has shown possible benefits of a keto diet for people with ADPKD. The researchers asked 131 people with ADPKD who had chosen to follow a keto diet for over 6 months about their symptoms. Nonetheless, 80% felt there was an improvement in their 'overall health' and 64% reported an improvement in ADPKD symptoms. More interesting still, almost two-thirds of the people had improved kidney function. In this group with an improvement, an average increase in estimated glomerular filtration rate (eGFR) of 3.6 ml/min/1.73 m2 was seen between two measures taken 6 months apart. As in the Cukoski study, some people on the keto diet got raised cholesterol.
A group in California has designed a ketogenic diet for people with ADPKD. This is called the Ren.Nu program. Based on the theory that a diet high in carbohydrate and animal protein might speed ADPKD progression, the Ren.Nu diet is a plant-focussed ketogenic diet.
Practical Considerations and Potential Side Effects
Following a keto diet can also make it hard to get sufficient nutrients if you’re not careful. Keto diets are renowned for being hard to stick to for more than a few months. In the second study above of 131 people, two-thirds of patients had periods of fatigue, hunger or ‘keto flu’. Constipation can be caused by a drop in fibre.
Without careful planning, people report feeling foggy, irritable, nauseous and tired. “In particular, low fiber intake can disrupt gut microbiota and lead to chronic constipation, while inadequate magnesium, vitamin C and potassium can contribute to muscle cramps, fatigue and weakened immune function,” explains Dr.
The keto diet can cause your blood pressure to drop in the short term due to a reduction in blood volume and changes in your fluid balance. Symptoms of low blood pressure include dizziness, lightheadedness or fainting, especially when standing up quickly. Following a keto diet can also cause your blood sugar to drop, which can be dangerous for people living with diabetes. Common symptoms of low blood sugar include weakness or shaking, sweating, a fast heartbeat and dizziness.
The Importance of Medical Supervision
All patients should discuss dietary changes with the physician and dietician, as the answer depends on a wholistic view of their health and disease state. Close medical supervision and monitoring of biochemical parameters is highly recommended.