In depth: should I feed my cat with chronic kidney disease a raw diet?

Updated: Mar 29



The internet is awash with recommendations, forthright opinions, and recipes for cats with chronic kidney disease (CKD). This is concerning – it's one thing for people to give bad nutritional advice for a healthy adult animal, but it's another thing when it's for an animal with a medical condition. Poor nutritional management of cats with CKD will shorten remaining lifespan and increase secondary complications - that has been well-established in cats, dogs, humans and many other species.


So in this post, I thought we would have a look at some common nutrition-related questions for cats with CKD, and also analyse an easily available free recipe and see what it looks like. This is a longer post, but if you are interested in feline nutrition, please do persist.


I'm going to get stuck into the hardest and most controversial question first, which is:


Should a cat with kidney disease be fed a protein-restricted diet?


This question has previously been a topic of contention and debate, even amongst board-certified veterinary nutritionists. Fortunately, some recent research appears to be making this a slightly more straight-forward question to try and answer. And that answer is, yes, cats with chronic kidney disease very likely benefit from a degree of protein restriction. Here's why.


Patients with chronic kidney disease accumulate many different toxins that have a wide range of detrimental systemic effects. They are called uraemic toxins, and some of these toxins are the products of fermentation of diet-derived amino acids by the gut microflora. An example is the well-researched uraemic toxin, indoxyl sulfate. Indole is produced from tryptophan by gut bacteria that express tryptophanase; this is converted to indoxyl sulfate in the liver.



So what does indoxyl sulfate do? Well, what doesn't it do! Research has shown that it adversely affects immune function, causes neuroinflammation, exhibits cardiovascular toxicity, advances the progression of kidney disease, is associated with increased mortality, and is a pathogenic factor for uraemic sarcopaenia or loss of lean muscle mass (Sato et al. 2016). This last one is interesting, as people often want to feed cats with CKD a high protein diet to try and prevent muscle loss.


It is well-established that human patients with CKD on very low protein diets have a significant decrease in uraemic toxins, which is likely due to decreased tryptophan, tyrosine and other amino acids in the diet. After one week on a very low protein diet, people with CKD had a 37% decrease in serum indoxyl sulfate (Marzocco et al. 2013). Poesen et al. (2015) also found that in healthy people, high dietary protein intake increases the concentration of indoxyl sulfate in both the serum and urine.


Two important studies on indoxyl sulfate and chronic kidney disease in cats have been done recently, and I'm sure there will be more to come. Summers et al. (2018) compared the faecal microbiome of cats with CKD, to that of healthy cats, and they also measured serum indoxyl sulfate in both groups. The authors found that cats with CKD had significantly decreased faecal bacterial diversity and richness. They also found that there were significantly higher indoxyl sulfate concentrations in IRIS stage 2 CKD cats, and also stages 3 and 4 CKD cats, in comparison to healthy control cats. Importantly, no significant difference was found in indoxyl sulfate concentrations between stage 2 CKD cats and stages 3 and 4 CKD cats, which appears to provide increased justification for earlier protein restriction (from early stage 2 onwards).


Chen et al. (2017) also found that plasma indoxyl sulfate was increased in dogs and cats with chronic kidney disease, particularly in IRIS stages 2 and 3. The authors state that "indoxyl sulfate concentrations were also correlated with the increase of blood urea nitrogen, serum creatinine, and phosphate and the decrease of haematocrit among cats." The research that we have (so far) therefore indicates that indoxyl sulfate does increase in cats with CKD, and whilst we don't yet have evidence that it has the same detrimental effects in cats as it does in other species, it seems highly likely.


An argument could be made that a high protein, raw meat-based diet is more digestible than an equivalent high protein, extruded commercial diet, so this could lead to relatively less fermentation of amino acids by gut bacteria and production of uraemic toxins. However, this still doesn't justify feeding excessively high protein raw (or commercial) diets.


Does it matter what proteins I feed?


Yes! Of course it does. Not all proteins are created equal. Aside from differences in their vitamin and mineral content, a key difference between proteins is their fat content. It is regrettable that kangaroo is often recommended for cats with CKD in Australia, because this is an extremely lean protein - it usually has only 0.5-1.5 grams of fat per 100 grams of meat. Compare this with something like standard beef mince, which has 10 grams of fat per 100 grams of meat.


Why does this matter? If you use extremely lean proteins like kangaroo or venison as the only, or predominant, proteins in your cat's homemade diet, you will significantly increase the protein and phosphorus content of the diet. You should now be able to see the problem with any product that comes with the instructions to "add to muscle meat". Chicken thigh is different to chicken breast. Beef is different to lamb. Salmon is different to tuna. Specifics matter when it comes to therapeutic diet formulation.


Should a cat with kidney disease be fed a phosphorus-restricted diet? How much phosphorus restriction is necessary? What supplements should I use?


Fortunately, the necessity for phosphorus restriction is much more widely acknowledged. Phosphate retention is the initiating factor for the development of many of the complications observed in chronic kidney disease, such as renal secondary hyperparathyroidism and bone and cardiovascular diseases. Multiple studies have demonstrated that dietary phosphorus restriction slows decline in renal function and increases mean survival time in cats with chronic kidney disease.


With respect to supplementation for home-prepared diets for cats with CKD, let me be as clear as I possibly can. The only phosphorus-restricted multivitamin/mineral supplement formulated specifically for cats that I would recommend, or be comfortable to use for my own cats, is BalanceIT Feline-K. The other option would be high quality human supplements. In my opinion, either BalanceIT or human supplements should be used as part of a therapeutic diet that has been carefully formulated for your cat and their specific needs.

Remember that you are feeding a homemade diet because you want your cat to have the best possible diet. The supplements used in the diet are the most critical component to get right - a small change in a food ingredient is unlikely to be harmful, however it's vital the your cat's supplements contain (a) what the company says they will, and (b) the correct amounts and types of all essential nutrients. Don't go to all the trouble of home-preparing and then settle for poorly formulated supplements, it's really not worth it.


Have a look at the analysis of a diet I formulated for my cat, Whirly, using 50% raw kangaroo meat and 50% raw skinless and boneless chicken thigh, plus a popular Australian 'meal completer' advertised as being suitable for cats with kidney disease. I followed the product instructions with respect to amounts and type of meat to use, and the amount of supplement to add, just as any other owner would:



The diet contains 71.2% of calories from protein, 22.7% calories from fat, and 6.1% of calories from carbohydrate. That's a lot of protein – 266.3% of the AAFCO minimum requirement for an adult cat. The diet also contains very little eicosopentaenoic acid (EPA) or docosahexaenoic acid (DHA); these are omega-3 fatty acids that have been shown to lower glomerular capillary

pressure, reduce proteinuria and slow decline in glomerular filtration rate. In fact, the omega-6 to omega-3 ratio is a very high 181.09!


However, the most concerning thing is the phosphorus content of this diet. Even though this product claims to produce a phosphorus-restricted diet, it clearly doesn't, with 1.83 grams per 1000 kcal ME, or 146.4% of the AAFCO minimum requirement, or 285.9% of the NRC minimum requirement. Properly formulated home-prepared renal diets typically contain less than 0.8 grams of phosphorus per 1000 kcal; Royal Canin Renal dry diet contains 0.8 grams, Hill's Prescription Diet k/d canned contains 0.85 grams.


Of course there are diets that contain more phosphorus than this one does. Protein-rich, raw meat diets are typically high in phosphorus, even without any bone, so manufacturers can argue that a diet like this contains "less phosphorus". In our opinion this is still not good enough; this product does not produce a phosphorus-restricted diet when used according to the (vague) instructions. It's true that we don't know exactly how much phosphorus restriction is ideal for cats with CKD, however there is no reason to exceed the AAFCO minimum requirement, and likely no reason to exceed the NRC minimum requirement either, particularly if the cat is hyperphosphataemic.


No problem, I hear you say, I'll just use a fattier meat to reduce the amount of phosphorus in my cat's diet, that's probably what the manufacturer would want me to do (even though it's not specified in the instructions). So here's the analysis again, for Whirly, using lamb shoulder, instead of kangaroo and chicken thigh:



As you can see, increasing the amount of fat versus lean meat in the diet does reduce the phosphorus content of the diet a lot, however it also reduces other essential nutrients as well - enough to make some of them moderately to severely deficient.


What about omega-3? Can't I just add some salmon or tuna? What oils should I add to my cat's diet?


You can probably guess the answer to this one. Like phosphorus and protein-restriction, it's important to do this properly. Canned and fresh fish do contain omega-3 fatty acids and in some cases this may be sufficient, however generally supplementary omega-3 fatty acids are required, in the form of fish oil, krill oil or calamari oil. Don't fall into the trap of thinking flaxseed or chia seed oil will do the trick; they do contain the omega-3 fatty acid, alpha-linolenic acid, but cats are poor at converting this to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), so these are not a good choice.


Unfortunately, there is a lack of research on the effect of omega-3 fatty acids on the progression of CKD in cats. However, there are two important papers by Brown et al. published in 1998 and 2000, on omega-3 fatty acids for dogs with CKD. The authors found that supplementation with omega-6 fatty acids hastened the decline of kidney function, and that omega-3 fatty were renoprotective. In an earlier study, the magnitude of proteinuria and the plasma concentrations of creatinine, cholesterol, and triglycerides were lower in the group of dogs fed a diet supplemented with fish oil. These papers provide some guidance as to why it's likely very beneficial to enrich the diet of cats with CKD with omega-3 fatty acids. They also provide some insight into what amount of supplementation is required, and what the optimal omega-6 to omega-3 ratio might be.


This ratio is the reason why just adding the same "dose" of fish oil to a cat's diet is not the best approach. A cat eating a diet of 100% chicken thigh will consume a lot more omega-6, compared with a diet of 100% lean kangaroo. Adding a small amount of fish oil to the kangaroo meat diet may be adequate to achieve a desirable omega-6 to omega-3 ratio, however it may not do much when added to the chicken thigh diet. If you want the best for your cat, it's important that the amount of omega-3 in the diet is adjusted with respect to the other ingredients in the diet.


Many recipes for cats with CKD have carbohydrate added, even online raw meat-based recipes? What's the story? Cats are carnivores.


Hopefully after reading the previous answers, you will agree that some degree of protein restriction is very likely to be beneficial for cats with CKD. To be able to decrease protein, we have to increase the other macronutrients: fat and/or carbohydrate. Creating a very low carbohydrate renal diet for a cat is possible, but it means that fat has to be extremely high. There is rarely a reason to employ this approach - the most successful option is to have a moderate to low carbohydrate diet, with moderate to high fat, and restricted protein. Remember that there is plenty of evidence that cats are able to digest and metabolise carbohydrates, if properly prepared.

Carbohydrates are also generally lower in phosphorus than proteins, so adding some carbohydrate helps to reduce phosphorus, as well as protein.


Another reason to add carbohydrate to a recipe for a cat with CKD is that you are often also adding two other valuable things: antioxidants and fibre. The benefits of adding fibre to a renal diet have, unfortunately, not been established in cats. However there is a lot of interesting research in other species, and it seems likely that fibre could benefit cats in the same way.


Studies have shown that animal models with chronic kidney disease exhibit an altered gut microbiota and increased gut permeability, which may be partially due to excessive luminal urea and its breakdown product, ammonia, reducing epithelial tight junction proteins in the colon. Dietary supplementation of resistant starches has been shown to decrease colonic pH and

improve gut barrier function, which may decrease translocation of harmful bacterial

products and metabolites, leading to a decreased inflammatory response in the kidneys (Vaziri et al. 2014; Kieffer et al. 2016). In people with CKD, a higher fibre intake is associated with decreased mortality (Krishnamurthy et al. 2012).


What about prescription renal diets? I read they are full of "fillers" and bad ingredients.


This is a misconception that arises from consideration of ingredients only, rather than nutrients. If you find yourself using the word "filler" in Facebook posts, or when talking to friends, ask yourself what you really mean? Do you mean that the diet contains carbohydrate? Or fibre? Do you mean it contains cardboard? Acrylic polymer? What exactly is a filler?


The word implies that commercial diets are full of ingredients that contribute nothing to the diet. Ingredients that have very little nutritional value, a bit like a supersize coke from McDonalds. Just because prescription renal diets contain carbohydrate sources, like rice, or wheat flour, doesn't mean those ingredients are contributing nothing of value to the diet. Different types of fat (animal fat or fish oil, for example) have value, as do different types of carbohydrate or fibre.


If you would prefer a home-prepared diet to a commercial prescription diet, that's fine, we obviously see the value in that. But please don't perpetuate the myth that prescription diets are harmful - there is no evidence to support this, and they can have huge benefits for cats with CKD, just like a correctly formulated home-prepared renal diet can.


Should I use a recipe for a raw or cooked renal diet that I found online?


To answer this question, let's have a look at one. The recipe below is taken from a Google search, from the first page of results that came up for me when I searched for "recipe cat kidney disease".


Here's the recipe:


1/4 cup chopped or ground raw chicken breast

1 cup cooked white rice

1 tablespoon omega-3 fish oil

1/8 teaspoon salt substitute (potassium chloride)

500 mg calcium (tablet or capsule without magnesium, vitamin D, or bonemeal)

1/4 human vitamin-mineral tablet

250 mg taurine


Before we get to the analysis - hopefully you will have noticed that the instruction to give "1/4 human vitamin-mineral tablet" is very vague! These multivitamins can vary hugely in terms of their nutrient profile, so it's really important to be specific with any required supplements. I used Blackmores Sustained Release Multi with Antioxidants - an easily available product in NZ and Australia. I used a 500 mg calcium carbonate tablet for the calcium and Nordic Naturals Omega-3 pet liquid as the added fish oil.


Anyway, here's the analysis:


I don't want to spend a lot of time discussing the deficiencies of this diet – the point is that there are many, and some of them are severe. Protein and phosphorus are excessively low - there's no need for this degree of restriction. Perhaps fortunately, this diet would probably be poorly palatable - I really hope people aren't feeding their cats with CKD poorly formulated diets like this.


It can be very frustrating to constantly see harmful nutritional advice being dispensed online. And let me be very clear - this is not an "anti raw diet" post. Most of my comments above also apply to cooked, home-prepared diets as well. The answer to the question in the title is, that it's certainly possible to formulate a raw, therapeutic diet for cats with chronic kidney disease, with appropriately restricted protein and phosphorus, omega- 3 enrichment, and adequate fibre, taurine and antioxidants .


However, it needs to be done with care and consideration of the individual cat's requirements. Raw CKD recipes don't work for every cat; some cats do better on a cooked renal diet, or on a commercial renal diet. Just because it's raw, doesn't make it good, or appropriate. It's important to consider all available options and seek expert advice when you make a decision regarding the best renal diet for your cat.


January 2022 update


It is fantastic to see how many people have read this post since it was originally written. We receive numerous emails about it everyday from dedicated cat owners, and we have also received some very constructive feedback. Before getting to that, I just want to add some updates to the science above.


A small study by Ephraim and Jewell was published in 2021; the title was "High Protein Consumption with Controlled Phosphorus Level Increases Plasma Concentrations of Uremic Toxins in Cats with Early Chronic Kidney Disease". 23 cats with CKD were included in the study, and they were fed three diets with differing protein over an 111 day period. The authors found that blood urea nitrogen (BUN), urine protein to creatinine ratio (UPC), plasma concentrations of microbial uraemic toxins such as 3-indoxyl sulfate and P-cresol sulfate, increased with higher protein concentration in food. Their conclusion was that "high protein foods may negatively affect the health of CKD cats even when they have controlled phosphorus level." This appears to provide further evidence for protein restriction, as discussed above in the original post.


Another important and relevant study was done by Geddes et al. in 2021 on "The effect of attenuating dietary phosphate restriction on blood ionized calcium concentrations in cats with chronic kidney disease and ionized hypercalcemia." The authors found that more moderate dietary phosphate restriction could result in normalisation of ionised calcium in some cats that develop hypercalcaemia while eating a commercial, highly phosphorus-restricted renal diet.

There are many more important published papers related to nutrition and chronic kidney disease; I'll try to add some more when I have time.


A practical update for Australian and New Zealand cat owners: unfortunately, due to a massive increase in shipping cost, BalanceIT supplements are now largely unaffordable, and we can no longer recommend these products. However, we can still formulate raw or cooked, personalised therapeutic recipes for cats with CKD, using high quality human supplements. For clients in the USA and other countries, we can continue to use and recommend BalanceIT products.


One reader did contact us with some feedback that they found the original post helpful. However, they mentioned that while our criticisms of other products and recipes were reasonable and constructive, we didn't provide any recommendations for online recipes that are actually safe to use. One reason for this is that we generally don't provide generic recipes, because the diets we formulate are personalised for the individual cat and their stage of disease, other medical conditions, and ingredient preferences.


Given the huge number of people that contact us everyday though, asking for help for their cat with CKD, we have decided to rethink this, and post one recipe for a homemade therapeutic diet here, suitable for cats with IRIS stage 2 or 3 chronic kidney disease. I really hope this will allow people to feed a safe, properly formulated homemade renal diet to their cat. This recipe can be fed to cats with proteinuria or hyperphosphataemia, but may not be the best choice for cats with hyperkalaemia or hypercalcaemia. Please talk to your local vet before changing your cat's diet. It is really important to get your vet's input. You can show your vet this blog post and the recipe and ask for any comments or thoughts.


Please be sure to monitor your cat's body weight regularly, to ensure he or she is eating enough. It is important that cats with CKD being fed a low protein diet consume enough calories per day, in order to prevent loss of muscle mass. A digital baby scale is usually the most accurate way for owner's to monitor their cat's body weight at home, every few days.


A few caveats before we get to the recipe:

1) The ingredients can not be changed, substituted or omitted. This is vital. If you swap proteins, or reduce the amount of carbohydrate, or change the fat/s, you may cause the recipe to become inappropriate at best, or harmful at worst. If you can't access these ingredients, or your cat doesn't like them, unfortunately you won't be able to use this recipe. Contact us to organise a referral and some personalised recipes, if you would like to.

2) Do not leave out the supplements or change them. Don't change the brand of the supplements, or the dose per batch. You could cause significant harm to your cat. If you can't buy these exact supplements, and include the required doses per batch, don't use the recipe.


The recipe is for a 1-kilogram batch of diet, which can be divided into daily meals. The diet will be highly digestible, with low protein (27.8% calories from protein), restricted phosphorus (0.71 g per MCal), high fat (54.8% calories from fat), moderate to low carbohydrate (17.4% calories from carbohydrate), and moderate to high moisture (70% water). It will be enriched with omega-3 fatty acids (omega-6 to omega-3 ratio of 2.9), antioxidants and have moderate soluble and insoluble fibre. Anyway, here is the recipe:



Chicken thigh and pink salmon with buttered rice, pumpkin and spinach


Required ingredients:


470 grams of skinless and boneless raw chicken thigh

30 grams of pink salmon (canned in spring water; including any bones and skin)

90 grams of salted butter (melted/softened)

220 grams of cooked white rice (medium or short grain preferred)

100 grams of raw pumpkin or butternut squash (peeled)

60 grams of raw spinach, silverbeet, chard or kale leaves (no stems)

1 gram (1 small pinch) of iodised table salt


Required supplements (per 1-kilogram batch):


Nordic Naturals omega-3 pet liquid: 7 mL

Now Foods psyllium husk powder: 5 grams

Now Foods taurine (1000 g) capsules: 2 capsules (contents only)

Thorne Research Basic B Complex capsules: 1 capsule (contents only)

Thorne Research BioMins with copper and iron: 6 capsules (contents only)

Now Foods calcium carbonate powder: 2 level teaspoons

Now Foods potassium chloride powder: 1/4 (one quarter) level teaspoon

Country Life choline tablets: 3 tablets (crushed)

Now Foods natural E-Oil: 2 drops


Preparation instructions:


Please use a digital kitchen scale and measuring spoons to measure all quantities very accurately. This is very important. Do not estimate amounts.

  1. Cook the white rice in water until very soft (overcooked), according to the manufacturer's instructions (you will likely need about 80 grams of uncooked rice). Allow to cool slightly, until warm, then weigh out required amount (220 grams) and mix through the melted butter (90 grams) until well-combined.

  2. Steam or microwave the chopped pumpkin and very finely chopped spinach leaves until very soft, then allow to cool and mash together.

  3. Depending on preference, weigh out the required amount of raw chicken thigh/s (470 grams), then either gently pan-fry it in a non-stick pan until cooked, or leave it raw. Dice or mince very finely, then set aside. We routinely recommend cooking all meat to reduce the risk of food-borne illness. However, some cats may prefer raw meat. Any meat fed raw must be very fresh and human-grade only.

  4. Combine the cooked white rice with the canned salmon (30 grams; drained weight) cooked pumpkin and spinach, and finely diced or minced chicken thigh (raw or cooked) and mix very thoroughly.

  5. Add the iodised salt, psyllium husk powder, and fish oil, and mix again.

  6. Finally, add the taurine capsules (contents only), B Complex capsule (contents only), BioMins capsules (contents only), vitamin E oil, calcium carbonate powder, potassium chloride powder (please measure this very carefully) and choline tablets (crushed to a powder).

  7. Be sure to mix together all the ingredients very well. The 1-kilogram batch of diet can be refrigerated or frozen until needed. When defrosting the food, do not heat it to a high temperature, just warm it gently and slowly, or defrost it in the fridge.

Here are the links to the supplements you will need to purchase:


Nordic Naturals omega-3 pet liquid:

https://www.nordic.com/products/omega-3-pet/

Available via NZ Health Store (https://www.nzhealthstore.co.nz/) for NZ and Australian clients. Order the liquid, not the capsules. The medium to large-breed dog product is more economical. Store in the fridge to minimise odour and prolong the shelf-life. If clients in Australia are not able to order this, please substitute PAW Blackmores fish oil 500: veterinary strength: (https://www.blackmores.com.au/products/pet-health/joint-care/paw-fish-oil-500-veterinary-strength)

Now Foods psyllium husk powder:

https://au.iherb.com/pr/now-foods-psyllium-husk-powder-12-oz-340-g/8934

Now Foods taurine (1000 mg) capsules:

https://au.iherb.com/pr/now-foods-taurine-double-strength-1-000-mg-100-veg-capsules/15787

Thorne Research Basic B Complex capsules:

https://au.iherb.com/pr/thorne-research-basic-b-complex-60-capsules/18791

Thorne Research BioMins with copper and iron:

https://au.iherb.com/pr/thorne-research-biomins-with-copper-iron-120-capsules/77122

Now Foods calcium carbonate powder:

https://au.iherb.com/pr/now-foods-calcium-carbonate-pure-powder-12-oz-340-g/480

Now Foods potassium chloride powder:

https://au.iherb.com/pr/now-foods-potassium-chloride-powder-8-oz-227-g/777

Country Life choline tablets:

https://au.iherb.com/pr/country-life-choline-100-tablets/1631

This supplement is occasionally out of stock. Sign up for notifications if it is, and order it as soon as you can.


Now Foods natural E-Oil:

https://au.iherb.com/pr/now-foods-natural-e-oil-antioxidant-protection-1-fl-oz-30-ml/565

Please store in the fridge to prolong the shelf-life.


Again - please include all ingredients and supplements exactly as per the recipe. Don't change anything. I understand it does look like an overwhelming number of supplements. Do keep in mind that while the initial cost of purchasing all the supplements may be quite high, many of them last for a long time, so the day-to-day cost is much more reasonable.


Cats can be very selective and most owners should expect to perform a gradual transition to a homemade therapeutic diet over 2-3 months (or longer sometimes!) Don't give up if you don't have immediate success; you will likely need to be patient and persistent. Remember to slightly warm the diet and serve it on a flat plate, to increase the appeal.


I hope this recipe is helpful, and also that it demonstrates that making a well-formulated homemade renal diet takes commitment and investment. If you really have no luck with this recipe, or your cat loves beef, or pork, or other proteins, we can formulate personalised recipes for you - there is more information on our referral process here:

https://www.veterinarynutritiongroup.com/for-veterinarians

Thank you for reading; we are passionate about feline nutrition and any questions or comments are very welcome.



Some more reading on kidney disease and nutrition:


Read the Summers et al. paper here: https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.15389

Read the Chen et al. paper here: http://www.cauvet.com/upload/accessory/20196/20196141610276258550.pdf

Read the Liao et al. paper here: https://onlinelibrary.wiley.com/doi/epdf/10.1111/jvim.15457

Read the Vaziri et al. paper here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260945/

Read the Kieffer et al. paper here: https://www.physiology.org/doi/full/10.1152/ajprenal.00513.2015

Read the Brown et al. paper here: https://www.ncbi.nlm.nih.gov/pubmed/10711867

Read the paper by Geddes et al. here: https://pubmed.ncbi.nlm.nih.gov/33527601/

Read the paper by Ephraim and Jewell here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258573/