Ketogenic metabolic therapy (KMT) is a medical nutrition therapy increasingly considered for various health conditions, especially those rooted in metabolic abnormalities. Chronic kidney disease (CKD), often stemming from overnutrition-related issues like hyperglycemia, insulin resistance, and diabetes mellitus, could potentially benefit from the carbohydrate restriction inherent in KMT. While standard pharmacological approaches to CKD primarily aim to slow its progression, studies suggest that KMT, in various forms, may be safe and even improve renal function in individuals with CKD.
Understanding Ketogenic Metabolic Therapy (KMT)
KMT, rather than just a "diet", refers to a medical nutrition therapy designed to address specific health conditions, including chronic kidney disease (CKD). The primary objective of KMT is to shift the body's metabolism into a state of ketosis, a normal physiological process where the body utilizes ketones (derived from fat) instead of glucose as its primary energy source.
The Process of Ketosis
When the body is deprived of carbohydrates, either through fasting or significant dietary restriction, it enters ketosis. This occurs after glycogen stores are depleted and insulin levels decrease, allowing fatty acids to be released from adipose tissues. The liver then converts some of these fatty acids into ketones, such as β-hydroxybutyrate (BHB) and acetoacetate.
KMT vs. Fasting
While fasting can induce ketosis, it is not a sustainable long-term solution. Ketogenic diets, developed over 150 years ago, offer a practical alternative. These diets typically restrict carbohydrate intake to approximately 20-50 grams per day, significantly less than the average consumption in most societies (100-300+ grams). To compensate for the reduced carbohydrate energy, dietary fat intake is increased.
The Role of Carbohydrate Restriction
The carbohydrate restriction in ketogenic diets leads to several metabolic changes: lower blood glucose levels, reduced insulin levels, glycogen depletion, fatty acid release, and ketone production. Unlike continuous fasting, ketogenic diets can be maintained for extended periods without causing nutrient deficiencies, as individuals continue to eat without major restrictions beyond carbohydrates.
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Historical Context and Modern Applications
Fasting, arguably the oldest form of medical nutrition therapy, has been practiced for centuries. KMT using ketogenic diets is not new; it was a routine therapy for diabetes mellitus and childhood epilepsy in pre-pharmacological times. Today, KMT is being researched for its potential in treating various non-communicable diseases (NCDs), including type 2 diabetes (T2D), cardiovascular and kidney disease, cancer, dementias, neurological disorders, mental illnesses, autoimmune diseases, and more.
KMT's Impact on Weight Loss and Inflammation
KMT's ability to utilize the body's fat stores makes it an effective therapeutic option for overweight and obese individuals, affecting associated comorbidities and NCDs. Beyond weight loss, KMT may also possess anti-inflammatory effects, largely attributed to the ketone body BHB. BHB acts not only as an energy carrier but also as a signaling molecule, activating the G protein-coupled receptor GPR109a at levels achieved during ketosis.
Addressing Misconceptions and Biases
Despite the growing body of evidence supporting KMT, many medical professionals, including dietitians and physicians, have limited training in this area, often focusing solely on its use in epilepsy treatment. This lack of knowledge leads to misunderstandings and biases regarding KMT, particularly in nephrology.
Common Misconceptions
Ketosis vs. Ketoacidosis: These are entirely different conditions. Ketosis is a normal physiological state with low blood glucose and moderate ketone levels, while ketoacidosis, primarily occurring in type 1 diabetes, is a dangerous pathological condition with extremely high levels of both glucose and ketones.
Carbohydrates as Essential Nutrients: This is incorrect. The human body can synthesize all necessary carbohydrates and adapt to low carbohydrate intake.
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The Brain's Dependence on Glucose: The body can adapt to use ketones instead of glucose.
Ketogenic Diets as High-Protein or Animal-Based Diets: While some ketogenic diets may be high in protein or animal products, the primary requirement is sufficient carbohydrate restriction and increased triglyceride intake. Plant-dominant (PLADO) and plant-focused ketogenic diets are increasingly used, aligning KMT with low-protein and plant-based approaches.
Equating "High-Fat Western" Diets with Ketogenic Diets: High-fat Western diets often contain high carbohydrate levels, preventing ketosis. A ketogenic diet, by definition, must have very low carbohydrate content and induce ketogenesis.
Investigator Biases
The field of nutrition research is susceptible to investigator biases, where researchers may promote their dietary preferences or be influenced by personal, religious, or ethical beliefs. Financial conflicts of interest, such as funding from specific food industries, can also skew research outcomes.
Rationale for KMT in CKD Treatment
Diabetes is a leading cause of CKD, with chronic hyperglycemia directly damaging the kidneys through vascular and tubular damage, inflammation, and fibrosis. Therefore, reducing hyperglycemia is a logical approach to prevent further renal deterioration.
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KMT's Impact on Hyperglycemia
KMT effectively lowers baseline blood glucose levels and reduces glucose spikes. Studies suggest that ketogenic diets are more effective than low-fat diets in glycemic control, weight loss, and reducing hypertension.
Reversing the Effects of the Standard American Diet (SAD)
The long-term, persistent hyperglycemia caused by the SAD leads to chronic hyperinsulinemia, insulin resistance, hypertension, inflammation, and renal tissue damage. KMT, by restricting carbohydrate intake, reverses these factors, leading to normoglycemia, lower insulin levels, and the reversal of insulin resistance and hypertension.
The Role of BHB
Lowering insulin levels allows lipolysis, where adipose tissues release fatty acids, which are then partially converted to BHB by the liver. BHB serves as the preferred energy substrate for most cells and tissues and acts as a signaling molecule with potent anti-inflammatory properties, notably inhibiting the NLRP3 inflammasome.
KMT vs. SGLT2 Inhibitors
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, widely prescribed for CKD, operate on a similar principle to KMT, albeit less effectively. These inhibitors cause renal excretion of glucose, effectively reducing the carbohydrate burden. KMT achieves a similar, and potentially greater, effect by directly reducing sugar and starch consumption.
Clinical Evidence and Studies
Preclinical studies have demonstrated the benefits of KMT in various renal conditions. For example, diabetic nephropathy in mouse models was completely reversed by a two-month ketogenic diet. Additionally, ketogenic diets have attenuated acute and chronic ischemic kidney injury in rats.
Human Studies
Several human studies have reported on the safety, feasibility, and efficacy of KMT in CKD. In general, these studies have shown that KMT is safe, feasible (with relatively high adherence rates), and can improve renal function.
Randomized Controlled Trial: A two-year intervention comparing a ketogenic diet (low carbohydrate, high fat/protein) with a Mediterranean diet and a conventional low-fat diet in overweight or obese participants with mild-moderate CKD (stages 1-3) showed that all dietary interventions led to weight loss and improved renal function.
Observational Prospective Study: A 15-week ketogenic diet intervention in 92 obese participants, including 38 with mild CKD (stage 2), resulted in significant fat weight loss, improved hypertension, reduced cholesterol and triglycerides, and remission of CKD in 27.7% of those with CKD, leading to an eGFR ≥90.
Retrospective Cohort Study: A retrospective cohort study of longitudinal change in kidney function in >2000 overweight and obese patients was conducted over a span of 19 years. More than 75% of the cohort had CKD (stage 1-3).
Randomized Controlled Study: A randomized controlled study of 40 individuals with T2D and mild-moderate CKD compared a 6-month intervention with a ketogenic, plant-based fasting-mimicking diet (5 consecutive days per month) to a Mediterranean diet. The KMT intervention led to numerous significant beneficial effects, including improved insulin resistance.
Potential Mechanisms of Kidney Protection
KD prevents and treats DKD by enhancing glucose and lipid metabolism, alleviating insulin resistance, and promoting weight loss.
Anti-Inflammatory Effects
KD or KD-induced BHB exerts anti-inflammatory effects on renal tissues and cells. BHB inhibits the NOD-like receptor protein inflammasome (NLRP3) by preventing K( +) efflux, which reduces ASC oligomerization and inhibits speck formation. Furthermore, BHB suppresses endoplasmic reticulum stress.
Anti-Fibrotic Effects
Emerging evidence suggests that KD and BHB delay DKD progression by regulating autophagy, as well as alleviating fibrosis.
Anti-Oxidative Stress Effects
BHB activates nuclear factor erythroid 2-related factor 2 (Nrf2), thereby mitigating oxidative stress and apoptosis.
Autophagy Effects
BHB activates AMPK and inhibits mTORC1, which promotes autophagy and lipolysis.
Practical Considerations and Potential Risks
While KMT shows promise, it's crucial to consider potential side effects and ensure proper implementation.
Potential Side Effects
Common side effects associated with KD include gastrointestinal discomfort (constipation, nausea, vomiting), hyperlipidemia, kidney stones, and, controversially, osteoporosis. Measures to mitigate these effects include increased fiber intake, medications for nausea, monitoring lipid profiles, and potassium citrate supplementation to prevent kidney stones.
Monitoring and Management
When employing KD for the treatment of kidney disease, it is essential to monitor the concentration of ketones in blood or urine to prevent the onset of ketoacidosis.
Individualized Approach
People with kidney disease need to follow an individualized diet prescribed by their doctor. According to Davita Kidney Care, people with kidney disease often need to consume a low-protein diet, which may not align with the type of keto you’re following.
Dietary Guidelines for CKD
When you have kidney disease, it is important to watch what you eat and drink because your kidneys cannot remove waste products as well as they should. A kidney-friendly eating plan can help you stay healthier and slow down damage to your kidneys.
Key Components of a Kidney-Friendly Eating Plan
- Protein: Eat the right amount and the right types of protein.
- Fat: Choose the right types of fat.
- Carbohydrates: Choose whole grain carbohydrates.
- Calories: Eat the right amount of calories to stay at a healthy weight.
- Sodium: Choose and prepare foods with less sodium (salt).
- Potassium: Choose foods with the right amount of potassium.
- Phosphorus: Limit phosphorus.
- Fluids: Limit fluid intake.
Portion Control
Good portion control or watching how much you eat is important in a kidney-friendly eating plan, because you may need to limit how much of certain things you eat and drink.
Adapting the Eating Plan to the Stage of CKD
How strict your eating plan should be depends on your stage of kidney disease. When you are in the early stages of CKD (Stages 1 and 2), you will have less limits on what you can eat. As your kidney disease gets worse (Stages 3, 4 and 5), your doctor may recommend that you limit potassium, phosphorus, and fluids.
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