How many grams of protein is equivalent to 1 tablet of ketoanalogue?

I saw this question on the Renal RD facebook page and it got my brain wheels spinning. How much protein is in a keto-analogue? How do you calculate it? Do you add it to the protein people are eating in their diet? And what are ketoanalogues anyways?

Well, in today’s post I am going to do my best to answer these questions. A key reference for this post is this review article on ketoanalogues. Let’s dive in!

What are ketoanalogues?

Ketoacid analogues are the precursors of amino acids, though they don’t have their nitrogen group attached. Consider that adults living with CKD have high amounts of circulating urea. Urea is a nitrogen atom with 4 hydrogens attached. This means that those with high urea don’t need to eat more nitrogen to build proteins.

Here is a nice picture of it from the article.

Adults who don’t get enough protein (amino acids) will go into negative nitrogen balance which can lead to cachexia. In this way, ketoanalogues provide those on a low protein diet with the building blocks (amino acids) that their bodies need to build and maintain muscles without adding more of what they don’t need – nitrogen!

What amino acids are in ketoanalogues?

While different formulations have been studied, most contain these 9 amino acids:

1. Isoleucine
2. Leucine
3. Phenylalanine
4. Valine
5. Hydroxyacid
6. Tryptophan
7. Threonine
8. Histidine
9. Tyrosine

When are ketoanalogues indicated?

According to the 2020 KDOQI nutrition practice guidelines, ketoanalogues are indicated in very low protein diets.

“In adults with CKD 3-5 who are metabolically stable, we recommend, under close clinical supervision, protein restriction with or without keto acid analogs, to reduce risk for end-stage kidney disease (ESKD)/death (1A) and improve quality of life (QoL) (2C):

a very low-protein diet providing 0.28–0.43 g dietary protein/kg body weight/day with additional keto acid/amino acid analogs to meet protein requirements (0.55–0.60 g/kg body weight/day)”

The KDOQI qualifiers for this statement are:

1. Adequate energy intake is required to promote protein sparing
2. Patients should be metabolically stable

If you are wondering if a low protein diet may be right for your patient, it may be helpful to check out my other blog posts on low protein diets, which you can find here.

Do you add the protein from ketoanalogues to dietary protein intake?

Yes! For patients on a very low protein diet, the goal is to bring the dietary protein intake down to 0.28-0.43g protein per kilogram of body weight, then top up to 0.55-0.6g/kg body weight with the keto-analogues.

Let’s do a sample calculation:

If we see a patient who weights 60kg and estimate their protein intake to be 25g per day, then their dietary protein intake is 25/60 = 0.416g/kg.

To get them to 0.55-0.60g protein per kg – this means we need to top them up with an additional (0.55-0.416 = ) 0.134g to (0.60-0.416 = ) 0.184g protein per kg body weight from a keto-analogue.

How do you dose ketoanalogues?

According to this document – there are two main ketoanalogues available for sale in the USA.

According to the Ketorena website, each scoop of powder contains 2.1g of keto and amino acids and the recommended starting dose is 0.1g/kg body weight per day. The tablet form contains 600mg keto-amino acids. 1 scoop of powder replaces 3 tablets.

According to the Ketosteril website, the dosing is 4-8 tablets three times daily for a 70kg adult. Their website links to several publications that used their products and when I reviewed a couple of these studies (Aparicio et al and Combe et al), the study protocols used a 0.3g/kg body weight dietary protein prescription supplemented with 1 tablet of Ketosteril per 5kg body weight.

Ketosteril does not provide a summary of how much protein or amino acids is in each tablet. They describe their tablets “characteristics” as:

• Calcium 3-methyl-2-oxovaleric acid (a-ketoanalogue of isoleucine, Ca-salt) 67 mg
• Calcium-methyl-2-oxovaleric acid (a-ketoanalogue of leucine, Ca-salt) 101 mg
• Calcium-2-oxo-3-phenylpropionic acid (a-ketoanalogue of phenylalanine, Ca-salt) 86 mg
• Calcium-3-methyl-2-oxobutyric acid (a-ketoanalogue of valine, Ca-salt) 68 mg
• Calcium-DL-2-hydroxy-4-(methylthio)-butyric acid (a-hydroxyanalogue ofmethionine) 59mg, Ca-salt 105 mg
• L-lysine acetate (= L-lysine 75 mg) 53 mg
• L-threonine 23 mg
• L-tryptophan 38 mg
• L-histidine 30 mg
• L-tyrosine

Which if I add these numbers all together = 571mg.

So how much ketoanalogues should we give to our patients?

Ok, lets go back to our example patient. Our patient weighs 60kg and is eating 0.416g/kg dietary protein. We want to supplement their protein intake by (0.134-0.184g/kg *60kg = ) 8-11g protein.

For ketorena, each scoop of powder is 2.1g – so that patient needs 3.8-5.2 scoops per day. I think we could round it off to 4-5 scoops per day. However, if we use the baseline dosing suggested from the ketorena website of 0.1g/kg this would be 0.1g * 60kg body weight = 6g. 6g/2.1g per scoop = 2.85 scoops, rounds up to 3 scoops.

For ketosteril, each tablet contains 0.571g – so that patient needs 14-19 tablets per day. If we use the same dosing as the studies using ketosteril at 1 tablet per 5g body weight (60kg/5kg =) the recommended number of tablets is 12.

Hmmm…. these numbers don’t add up

Houston, we have a problem…. these numbers don’t add up. How do we reconcile the package dosing recommendations for ketorena and the KDOQI nutrition practice guidelines? According to our 60kg person example, to top up ketoanalogues to require dose, means we are giving 33-66% more than the package directions. For ketosteril this recommendation falls within the recommendation of 4-8 three times daily (12-24 per day).

I couldn’t find any additional resources on the internet that would help practicing dietitians dose ketoanalogues based on dietary assessment. There there is this comprehensive blog post and an RD course. Though my questions remain unanswered. Has anyone taken the course? Or does anyone have any additional resources tips and tricks for dosing ketoanalogues?

I would be curious to know!