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Written by: Mugdha Rairikar MD, Shweta Shah MD
Infographics:Mugdha Rairikar MD, Salar Bani Hani, MD
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
A 6 yr-old female with static encephalopathy is referred to the nephrology clinic for blood-speckled urine in the diaper. The patient has a history of non-accidental head trauma in infancy leading to global developmental delay and refractory epilepsy on clobazam, levetiracetam, and zonisamide. She was started on a ketogenic diet at the age of 4 years, which led to an improvement in seizure frequency. The development of acidosis, after initiation of the ketogenic diet, prompted the initiation of potassium bicarbonate therapy. Unfortunately, due to insurance issues, the patient stopped getting potassium bicarbonate 6 months prior to presentation. Urinalysis showed 3+ blood with 15-20 RBC/high power field (hpf) and an elevated urine calcium:creatinine ratio. Kidney and bladder ultrasound showed bilateral nephrocalcinosis. The basic metabolic profile was notable for a bicarbonate of 18 meq/dL, but was otherwise unremarkable.
How, when and why does a nephrologist come into the picture when a patient is on a ketogenic diet? Let’s turn a few stones on this topic.
Ketogenic diet (KD), popularly known as ‘keto diet,’ has been around for more than a century. Mentions of fasting to treat epilepsy can be found as early as 400 BC during Hippocrates’s time. References to fasting or starvation as a cure to treat convulsions were found in Biblical times as well. The keto diet as we know today was first coined and described in 1921 by Dr. Russell Morse Wilder at the Mayo Clinic when he performed the first trial in pediatric epilepsy. KD became widespread for treating epilepsy in the 1920s and 1930s until phenytoin was discovered in 1938. KD again regained popularity in the 1990s for refractory epilepsy, with Hollywood partly influencing this renewed interest. Jim Abrahams, a Hollywood producer, started the Charlie Foundation in 1994 to help promote the diet based upon his experience with his son’s severe epilepsy. Charlie Abrahams, at 11 months of age, suffered from uncontrollable epilepsy despite multiple antiepileptics. They tried KD as a last resort and noticed seizure control within weeks. He remained on KD for 5 years and has since been on a normal diet with no more seizures and no antiepileptics. The story featured on NBC's Dateline, and the movie ‘First Do No Harm’ further revived the popularity and interest in KD.
Keto diet is a high-fat, low-carbohydrate, and moderate-protein diet, commonly used for treating intractable epilepsy.
Numerous theories have been proposed for the mechanism of seizure control. It is likely a combination of multiple factors that reduce hyperexcitability of neurons by altering blood and neural metabolic pathways.
Induction of ketosis by increasing fatty acid oxidation and generation of ketone bodies by activating acetyl coenzyme A. Ketosis and ketone bodies are deemed to be protective in refractory epilepsy by altering neurotransmitter release and seizure sensitivity.
Ketosis enhances anaerobic metabolism and reduces availability of glucose mediated energy reserves needed for seizure activity producing an anticonvulsant effect.
Synaptic stabilization by increasing the levels of GABA, a major inhibitory neurotransmitter.
Alteration of gut microbiota and increased production of GABA by beneficial microbiomes.
The utility of keto diet in disorders like diabetes, obesity, Alzheimer’s disease, and chronic kidney disease is also being investigated.
There are different types of keto diet depending upon the variability of fats, carbohydrates, and proteins (Figure 1).
Classic/Traditional:
Fats : (protein + carbohydrate) = 4:1 to 3:1
No calorie or fluid restriction
Most aggressive, difficult to maintain, high attrition rate
Medium-chain triglyceride (MCT)
30 - 60% energy from MCT
Better flexibility, more palatable, but more gastrointestinal side effects
Modified Atkins diet
65% fat, 30% protein, 5% carbohydrate
Modified from Atkins diet for weight loss
Food choices similar to classic keto diet, without the precision
Carbohydrates restricted to 10 gm/day in the first month, subsequently > 20gm/day
Low glycemic index
Most liberalized regimen
Low carbohydrate diet with foods having glycemic indices < 50
Figure 1. Types of ketogenic diet
Effects of KD on metabolism
Lipid metabolism
Lower total cholesterol, and higher high-density lipoproteins decrease the risk for atherosclerosis. In addition, there is attenuated cholesterol synthesis due to low insulin levels.
Low insulin levels and heightened sensitivity to insulin enhances fat metabolism and fibroblast growth factor -1 mediated clearance of triglyceride.
Lastly, a low insulin-to-glucagon ratio leads to lower glucose production.
Ketogenic process
Continuous state of ketosis results from low glycolytic ATP from glucose, thereby activating mitochondrial oxidative metabolic pathways.
Gut microbiome
KD promotes the growth of anti-inflammatory gut bacilli (Akkermansia and Parabacteroides), decreasing inflammatory gut chemokines (interleukins) by downregulating γ-glutamyl transpeptidase and glutamate production.
Figure 2. Effects of ketogenic diet on metabolism
Ketogenic diet and effects on Kidneys:
Kidney stones/ Nephrolithiasis:
The key contributing factor to the formation of stones is acidosis induced by KD. Acidosis promotes kidney stone formation by lowering urine pH levels and urinary citrate while potentially increasing urinary calcium levels and the risk of developing albuminuria. Nephrolithiasis is the most common side effect seen in patients on the KD for greater than two years. While the yearly incidence of nephrolithiasis in the general population is 0.3% to 0.5 %, the incidence of nephrolithiasis in children on KD has been noted to be about 5.8%.
Mechanism of stone formation:
The exact mechanisms of stone formation are unknown. It is likely a combination of various metabolic abnormalities precipitating the formation of stone. Hypocitraturia and urine acidification are crucial for stone formation.
The stone composition in patients with the keto diet is uric acid (most common), calcium oxalate, or mixed calcium oxalate/uric acid. The underlying mechanism proposed for nephrolithiasis in KD, shown in figure 3, is as follows:
Chronic metabolic acidosis from ketosis leads to decreased calcium reabsorption in renal tubules, causing hypercalciuria
Acidosis increases proximal tubular reabsorption of citrate resulting in hypocitraturia. Both of these factors together predispose to calcium stone formation
The low urinary pH favors uric acid and calcium oxalate stone formation. Uric acid stone can be a nidus for calcium stones thus perpetuating the risk.
KD is reported to interfere with the thirst mechanism, often leading to dehydration, the biggest risk factor for kidney stones.
Simultaneous use of carbonic anhydrase inhibitor, and antiepileptics like zonisamide or topiramate with carbonic-anhydrase inhibitor activity, could further increase the risk for kidney stones.
Finally, bone demineralisation with chronic acidosis on KD described in some studies, could cause hypercalcemia and worsen hypercalciuria.
Figure 3. Pathophysiology of stone formation in ketogenic diet
Management guidelines for nephrolithiasis by the International Ketogenic Diet Study group
Evaluate for personal and family history of kidney stones – renal ultrasound and renal referral if positive.
Oral potassium citrate – preventing urinary acidification is an effective treatment for kidney stones in children. Higher urine pH increases calcium solubility. In addition, it helps decrease the availability of free calcium, further reducing the stone risk. Citrate is recommended for patients with a history of kidney stones or an identified risk, but the efficacy of empiric therapy has not been studied in prospective studies.
Since the keto diet works by restricting carbohydrates and sugars, it is essential to check the preparation of medications. Most liquid medications contain some carbohydrate as a non-active ingredient, which might lead to failure in achieving the desired ketosis level. For example, the commonly used medications in renal tubular acidosis, including sodium citrate or sodium-potassium citrate liquid formulations are commonly combined with sugar solutions for palatability. Powders or tablets are preferred in this situation. Potassium bicarbonate powder, Effer-K (Potassium bicarbonate) tablets, or Urocit-K (potassium citrate) tablets are often used. Pre-emptive administration of these medications with the initiation of KD is recommended to prevent kidney stones and achieve ketosis sooner.
Liberal fluid intake of 2 - 2.5L is encouraged in adolescents to prevent kidney stones. In younger children, intake amounting to their maintenance fluid requirement is recommended. Liberal fluid intake does not affect the ketosis needed to reduce seizure frequency and is well tolerated.
Continued assessment of stone risk in patients who do not have stones with monitoring of serum electrolytes, uric acid, urinalysis, and urinary calcium excretion is recommended.
It is important to realize the need to work closely with an epileptologist, a dietician, and a pharmacist well-versed with the KD.
Figure 4. Management of kidney stones on ketogenic diet
CKD and Dietary Restrictions:
There are challenges in designing and maintaining KD in patients with advanced CKD who are often on a protein, phosphorus, sodium, and/or potassium restricted diet.
Long-term sustainability and cost of the diet can be restrictive.
KD could contribute to already poor nutritional status in CKD or end stage kidney disease patients with existing nutritional challenges.
KD may increase mortality, especially in those with cardiac comorbidities in the long run.
Miscellaneous effects:
Muscle pain, alteration in bowel habits, keto-flu, loss of energy, induction of insulin resistance in the liver, and a deficiency of micronutrients have been described.
Altered insulin and fat metabolism could predispose patients to rapid CKD progression.
A recent study showed that long-term KD increases serum creatinine levels. There is significant concern that high protein diet and acidosis associated with ketogenic diet might actually hasten CKD progression. However, definitive data is not yet available.
Some animal studies propose higher RAAS activation with ketogenic diet leading to hypertension. Aggravation of baseline hypertension through the NF-kB pathway and endothelial dysfunction has also been described in animal models.
On the other hand, ketogenic diet attenuates inflammation via reactive oxygen species, NF-kB signaling, which could be beneficial in slowing CKD progression and reducing CV risk. However, this needs to be explored further.
Dietary interventions leading to ketosis development have been shown to slow cyst growth in the mouse model of ADPKD. The Keto-ADPKD trial is underway to study this in humans.
Although there is not enough study on the effect of ketogenic diet on bone mineral metabolism, there is some concern that it adversely affects bone health in patients with intractable epilepsy who are treated with KD. Recently, ketogenic hypercalcemia is seen as a complication of KD, likely due to low osteoblast turn over prompting close monitoring.
The kidney effects and alterations in the metabolic milieu from ketogenic diet or the K2 dynamic as we called it, is thus not limited to nephrolithiasis but poses additional challenges in patients with CKD. However, further studies are needed to validate the association with CKD and understand the underlying mechanisms.
Take Home Message:
Nephrolithiasis is not uncommon, and can be a debilitating and recurring issue in children on KD.
Patients on KD need a multidisciplinary approach with various sub-specialties including nephrology.
Early referral, identification and prevention of kidney stones with close monitoring of kidney function, stone risk and bone health parameters are integral to the overall care plan.
Reviewed by Corina Teodosiu, Swasti Chaturvedi, Md. Abdul Qader, S. Sudha Mannemuddhu, Brian Rifkin, Roshan George, Sophia Ambruso
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.