Monthly Archives: November 2010

Kidney stones are a frequent occurrence on the ketogenic diet for epilepsy. [1, 2, 3] About 1 in 20 children on the ketogenic diet develop kidney stones per year, compared with one in several thousand among the general population. [4] On children who follow the ketogenic diet for six years, the incidence of kidney stones is about 25% [5].

A 100-fold odds ratio is hardly ever seen in medicine. There must be some fundamental cause of kidney stones that is dramatically promoted by clinical ketogenic diets.

Just over half of ketogenic diet kidney stones are composed of uric acid and just under half of calcium oxalate mixed with calcium phosphate or uric acid. Among the general public, about 85% of stones are calcium oxalate mixes and about 10% are uric acid.  So, roughly speaking, uric acid kidney stones are 500-fold more frequent on the ketogenic diet and calcium oxalate stones are 50-fold more frequent.

Causes are Poorly Understood

In the nephrology literature, kidney stones are a rather mysterious condition.

Wikipedia has a summary of the reasons offered in the literature for high stone formation on the ketogenic diet [4]:

Kidney stone formation (nephrolithiasis) is associated with the diet for four reasons:

• Excess calcium in the urine (hypercalciuria) occurs due to increased bone demineralisation with acidosis. Bones are mainly composed of calcium phosphate. The phosphate reacts with the acid, and the calcium is excreted by the kidneys.
• Hypocitraturia: the urine has an abnormally low concentration of citrate, which normally helps to dissolve free calcium.
• The urine has a low pH, which stops uric acid from dissolving, leading to crystals that act as a nidus for calcium stone formation.
• Many institutions traditionally restricted the water intake of patients on the diet to 80% of normal daily needs; this practice is no longer encouraged.

These are not satisfying explanations. The last three factors focus on the solubility of uric acid or calcium in the urine; the first on availability of calcium, one of the most abundant minerals in the body.

There is no consideration of the sources of uric acid, oxalate, or calcium phosphate.

Two of the factors focus on urine acidity, but alkalinizing diets have only a modest effect on stone formation. In the Health Professionals Study and Nurses Health Study I and II, covering about 240,000 health professionals, people with the lowest scores for a DASH-style diet (an alkalinizing diet high in fruits, vegetables, nuts, and legumes) had a kidney stone risk less than double that of those with the highest DASH-style scores. [6]

On ketogenic diets specifically, supplementation with potassium citrate to alkalinize the urine and provide citrate reduced the stone formation rate by a factor of 3. [3] They were still more than 30-fold more frequent than in the general population.

It seems the medical community is still unaware of some primary causes of stone formation.

Uric Acid Production

One difference between a ketogenic (or zero-carb) diet and a normal diet is the high rate of protein metabolism. If both glucose and ketones are generated from protein, then over 150 g protein per day is consumed in gluconeogenesis and ketogenesis. This releases a substantial amount of nitrogen. While urea is the main pathway for nitrogen disposal, uric acid is the excretion pathway for 1% to 3% of nitrogen. [7]

This suggests that ketogenic dieters produce an extra 1 to 3 g/day uric acid from protein metabolism. A normal person excretes about 0.6 g/day. [8]

In addition to kidney stones, excess uric acid production may lead to gout. Some Atkins and low-carb Paleo dieters have contracted gout.

Oxalate Production

Our last post (on scurvy) argued that very low-carb dieters are probably inefficient at recycling vitamin C from its oxidized form, dehydroascorbic acid or DHAA.

If DHAA is not getting recycled into vitamin C, then it is being degraded. Here is its degradation pathway:

The degradation of vitamin C in mammals is initiated by the hydrolysis of dehydroascorbate to 2,3-diketo-l-gulonate, which is spontaneously degraded to oxalate, CO(2) and l-erythrulose. [9]

Oxalate is a waste material that has to be excreted in the kidneys. Vitamin C degradation is a major – in infections, probably the largest – source of oxalate in the kidneys:

Blood oxalate derives from diet, degradation of ascorbate, and production by the liver and erythrocytes. [10]

Since the loss rate from vitamin C degradation can reach 100 g/day in severe infections, and most of that mass is excreted as oxalate, it is apparent that a very low-carb dieter who has active infections, as did I and KM in the scurvy post, or some other oxidizing stress such as injury or cancer, may easily excrete grams of oxalate per day, with the amount limited by vitamin C intake.

Dehydration and Loss of Electrolytes

Excretion of oxalate consumes both electrolytes, primarily salt, and water:

In mammals, oxalate is a terminal metabolite that must be excreted or sequestered. The kidneys are the primary route of excretion and the site of oxalate’s only known function. Oxalate stimulates the uptake of chloride, water, and sodium by the proximal tubule through the exchange of oxalate for sulfate or chloride via the solute carrier SLC26A6. [10]

Salt and water are also needed by the kidneys to excrete urea and uric acid.

Personally, I found that my salt needs increased dramatically on a zero-carb diet. I needed at least a teaspoon per day of salt when zero-carbing, compared to less than a quarter-teaspoon when eating carbs.

As a result of loss of salt and water, low-carb dieters tend to become dehydrated. This is also a widely-observed side effect on ketogenic diets.

We’ve all seen what happens to urine when we’re dehydrated: it becomes colorful due to high concentrations of dissolved compounds.

As urine becomes saturated, it no longer possible for uric acid and oxalate to dissolve. They precipitate out and initial deposits nucleate further deposits to form kidney stones.

Polyunsaturated Fats and Kidney Stones

That brings us to another factor that promotes kidney stones: high omega-3 polyunsaturated fat consumption.

Here’s the data:

Older women (NHS I) in the highest quintile of EPA and DHA intake had a multivariate relative risk of 1.28 (95% confidence interval, 1.04 to 1.56; P for trend = 0.04) of stone formation compared with women in the lowest quintile. [11]

Eating omega-3 fats promotes calcium oxalate kidney stones about as much as eating oxalate. The top quintile of dietary oxalate intake has a relative risk of 1.22. [12]  (The top dietary source of oxalate is spinach, by the way.)

So what about EPA and DHA promotes kidney stone formation?  A clue comes from julianne of Julianne’s Paleo & Zone Nutrition Blog; she made a very interesting comment:

A few years ago I started taking a high dose of Omega 3, because of joint inflammation, and other issues. This made big difference for about 3 months, then seemed to not work any more. I talked to a nutritionist friend and she pointed out that according to Andrew Stoll (The Omega 3 Connection) you must take 1000 mg vit C and 500 iu vit E daily or the omega 3 becomes oxidised in your body (cell membranes) and ineffective. I started taking both and in days was back to the original anti-inflammatory effectiveness of omega 3. I have since talked to others about this – for example a psychiatrist whose clients did well on omega 3 for 3 months and then it became ineffective.

Paleo advice from many is to consume a high dose of omega 3, and at the same time reduce carbs. I am wondering if there are people suffering vit C depletion as a result of increased omega 3 consumption as well as too low carbs?

EPA and DHA have a lot of fragile carbon double bonds – 5 and 6 respectively – and are easily oxidized. It’s quite plausible that this lipid peroxidation can lead to oxidation and degradation of vitamin C.

If so, then higher EPA and DHA consumption would increase the flux of oxalate through the kidneys and raise the risk of calcium oxalate stones. It makes sense that the effect is strongest in the elderly, who tend to have the worst antioxidant status.

What Does This Tell Us About the Cause of Stones in the General Population?

Since most kidney stones afflicting the general public are calcium oxalate stones, it seems likely that vitamin C degradation may be the major source of raw material for kidney stones.

If so, then the risk of kidney stones can be greatly reduced by dietary and nutritional steps.

First, the rate of oxidation can be slowed by higher intake of antioxidants such as:

• Glutathione and precursors such as N-acetylcysteine;
• Selenium for glutathione peroxidase;
• Zinc and copper for superoxide dismutase;
• Coenzyme Q10 for lipid protection;
• Alpha lipoid acid;
• Colorful vegetables and berries.

Vitamin C supplementation has mixed effects: its antioxidant effect is beneficial but its degradation is harmful.

Second, electrolyte and water consumption are important. Salt is especially important.

Finally, alkalinizing compounds like lemon juice or other citrate sources can increase the solubility of uric acid.

Conclusion

Zero-carb dieters are at risk for

• Excess renal oxalate from failure to recycle vitamin C;
• Excess renal uric acid from disposal of nitrogen products of gluconeogenesis and ketogenesis;
• Salt and other electrolyte deficiencies from excretion of oxalate, urea and uric acid; and
• Dehydration.

These four conditions dramatically elevate the risk of kidney stones.

To remedy these deficiencies, we recommend that everyone who fasts or who follows a zero-carb diet obtain dietary and supplemental antioxidants, eat salt and other electrolytes, and drink lots of water.

Also, unless there is a therapeutic reason to restrict carbohydrates, it is best to obtain about 20% of calories from carbs in order to relieve the need to manufacture glucose and ketones from protein. This will substantially reduce uric acid excretion. If it also reduces vitamin C degradation rates, as we argued in our last post, then it will substantially reduce oxalate excretion as well.

Related Posts

Other posts in this series:

1. Dangers of Zero-Carb Diets, I: Can There Be a Carbohydrate Deficiency? Nov 10, 2010.
2. Dangers of Zero-Carb Diets, II: Mucus Deficiency and Gastrointestinal Cancers A Nov 15, 2010.
3. Danger of Zero-Carb Diets III: Scurvy Nov 20, 2010.

References

[1] Furth SL et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol. 2000 Nov;15(1-2):125-8. http://pmid.us/11095028.

[2] Herzberg GZ et al. Urolithiasis associated with the ketogenic diet. J Pediatr. 1990 Nov;117(5):743-5. http://pmid.us/2231206.

[3] Sampath A et al. Kidney stones and the ketogenic diet: risk factors and prevention. J Child Neurol. 2007 Apr;22(4):375-8. http://pmid.us/17621514.

[4] “Ketogenic diet,” Wikipedia, http://en.wikipedia.org/wiki/Ketogenic_diet.

[5] Groesbeck DK et al. Long-term use of the ketogenic diet. Dev Med Child Neurol. 2006 Dec;48(12):978-81. http://pmid.us/17109786.

[6] Taylor EN et al. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol. 2009 Oct;20(10):2253-9. http://pmid.us/19679672.

[7] Gutman AB. Significance of uric acid as a nitrogenous waste in vertebrate evolution. Arthritis Rheum. 1965 Oct;8(5):614-26. http://pmid.us/5892984.

[8] Boyle JA et al. Serum uric acid levels in normal pregnancy with observations on the renal excretion of urate in pregnancy. J Clin Pathol. 1966 Sep;19(5):501-3. http://pmid.us/5919366.

[9] Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007 Jan;274(1):1-22. http://pmid.us/17222174.

[10] Marengo SR, Romani AM. Oxalate in renal stone disease: the terminal metabolite that just won’t go away. Nat Clin Pract Nephrol. 2008 Jul;4(7):368-77. http://pmid.us/18523430.

[11] Taylor EN et al. Fatty acid intake and incident nephrolithiasis. Am J Kidney Dis. 2005 Feb;45(2):267-74. http://pmid.us/15685503.

[12] Taylor EN, Curhan GC. Oxalate intake and the risk for nephrolithiasis. J Am Soc Nephrol. 2007 Jul;18(7):2198-204. http://pmid.us/17538185.