A reader recently asked me to investigate yet another supplement product, this one marketed for treatment of kidney disease in dogs and cats. While there are thousands of such products, and a thorough investigation of each isn’t possible, there were some interesting features to this particular product, so I spent some time looking into it.
What Is It?
The short answer is, “Who knows?” The product is called RenAvast™, and first on the list of red flags of quackery is the fact that the company won’t say exactly what it contains. The ingredients are listed as “a proprietary combination of amino acids and peptides.” While I understand that intellectual property concerns are often valid, it is also appropriate to be extremely wary of any medical therapy that contains secret ingredients. The American Veterinary Medical Association (AVMA) Principles of Veterinary Medical Ethics specifically identifies selling or using such products as unethical:
It is unethical for veterinarians to promote, sell, prescribe, dispense, or use secret remedies or any other product for which they do not know the ingredients.
I did find one site purporting to have identified the ingredients as, “300mg: L-Aspartic, L-Carnosine, L-Glutamic Acid, L-Glutamine, Glycine, L-Arginine, L-Histadine,” though I have not been able to confirm that on any site associated with the company. The inventor of the product describes it in a radio interview as “amino acids and a peptide,” but again doesn’t provide any more details.
The company research report describes the substance as:
a powerful ROS scavenger, a cytoprotective agent which reduces damage to proximal renal tubules and increases glomerular filtration rate (GFR), stimulates gluconeogenesis and suppresses proteolysis in skeletal muscle, has strong anti-inflammatory properties, is a precursor for NO production, and induces BMP-7…
It is impossible to assess these claims without knowing what the ingredients actually are. Elsewhere in the document, reference is made to seven different “biomolecules” in the product and their supposed functions. The claims made here for these functions are supported with a reference to an unnamed publication listed in the references as “PLAW 104-294.” I have no idea what this means.
There is reference to another study which showed that the molecule BMP-7 has some effect on damaged kidney cells in mice with artificially induced renal failure. Supposedly, biomolecule 7” in RenAvast™ induces production of BMP-7, though no evidence for this is provided. This tenuous connection between the mystery ingredients in RenAvast™ and kidney disease hardly justifies using the product in actual patients in the absence of additional pre-clinical research and clinical trials. As we will see, there really aren’t any such trials.
The company makes many bold claims for the product despite the lack of tangible support for them:
RENAVAST™ MECHANISM OF ACTION
Protects cells, particularly in renal tubules.
Increases glomerular filtration rate (GFR).
Decreases protein breakdown, especially in skeletal muscles.
Has a strong anti-inflammatory effect.
Decreases renal blood pressure.
Increases renal vasodilation.
Increases hormone that promotes renal tissue repair.
[RenAvast™ is] SAFE – More than 4,000,000 doses have been given to dogs and cats with no negative side effects reported… It is 100% safe with no side effects.
[It is] scientifically proven in an open-ended two year clinical study to supplement and promote healthy renal function. Unlike other products and drugs, RenAvast™ does not treat the symptoms of renal failure, it treats the cause.
Along with these confident claims is, of course the required Quack Miranda Warning which reminds us that the company has not felt it necessary to provide the FDA with any real evidence to support them: “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.” It always amazes me that companies put this disclaimer on their sites and then loudly (and illegally) proclaim that their products do treat disease.
The chutzpah necessary to do this is especially impressive in this case since the company, BioHealth Solutions, has already been warned by the FDA that their marketing of RenAvast™ is illegal:
August 1, 2012
This letter concerns your firm’s marketing of the product RenAvast™. The U.S. Food and Drug Administration (FDA) reviewed your website at the internet address www.RenAvast™.com, where you promote and sell this product. We have determined that RenAvast™ is intended for use in the mitigation, treatment, or prevention of disease in animals, which makes it a drug under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. § 321(g)(1)(B)]. Further, as discussed below, this product is an unapproved new animal drug as defined by the FD&C Act and your marketing of it therefore violates the law.
Statements on your website that show these intended uses of your product include, but are not limited to, the following:
• RenAvast™™ can halt the progression of chronic renal failure
• RenAvast™™ may reverse the effects of chronic renal failure
• RenAvast™™ may help prevent kidney disease in healthy cats
• RenAvast™™ is a new, highly effective compound that has been proven through a two-year clinical study to halt the progression of Chronic Renal Failure (CRF) in cats and improve overall kidney function
• Unlike other products and drugs, RenAvast™™ does not treat the symptoms of renal failure, it treats the cause
• RenAvast™™ was highly successful in halting the progression of Chronic Renal Failure and in most cases improved kidney function.
• Finally a solution for cats with Chronic Renal Failure
• A two-year open ended clinical study proves that RenAvast™ can halt the decline in kidney function
• Until now, veterinary medicine could only manage symptoms in an attempt to maintain quality of life while the disease progressed relentlessly onward. All of that has now changed
• Chronic Renal Failure is no longer a death sentence
Because RenAvast™ is intended to mitigate, treat, or prevent disease in animals, it is a drug within the meaning of section 201(g)(1)(B) of the FD&C Act. Further, this product is a new animal drug, as defined by section 201(v) of the FD&C Act, [21 U.S.C. § 321(v)], because it is not generally recognized among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling.
To be legally marketed, a new animal drug must have an approved new animal drug application, conditionally approved new animal drug application, or index listing under sections 512, 571, and 572 of the FD&C Act [21 U.S.C. §§ 360b, 360ccc, and 360ccc-1]. RenAvast™ is not approved or listed by the FDA, and therefore the product is considered unsafe under section 512(a) of the FD&C Act, [21 U.S.C. § 360b(a)], and adulterated under section 501(a)(5) of the FD&C Act [21 U.S.C. § 351(a)(5)]. Introduction of an adulterated drug into interstate commerce is prohibited under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].
This letter is not intended to be an all-inclusive review of your products and their promotion. It is your responsibility to ensure that all of your products are in compliance with the Act and its implementing regulations. Failure to promptly correct the violations specified above may result in enforcement action without further notice. Enforcement action may include seizure of violative products and/or injunction against the manufacturers and distributors of violative products.
You should notify this office, in writing, within fifteen (15) working days of the receipt of this letter of the steps you have taken to bring your firm into compliance with the law. Your response should include any documentation necessary to show that correction has been achieved. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the date by which the corrections will be completed. Include copies of any available documentation demonstrating that corrections have been made.
Unfortunately, as I’ve discussed previously, regulatory control of veterinary quackery is not very effective. This warning appears to be more than a year old, and I was not able to find any information regarding how it was resolved. Regardless, the company continues to make clear treatment claims despite the warning and disclaimer.
Does It Work? Is It Safe?
The general claims about mechanism of action cannot be evaluated without any information about what is in the product. If there is any plausible reason to think it might work based on in vitro or lab animal studies, we cannot determine this without knowing what is in it.
Likewise, the safety cannot be assessed simply by accepting the company’s word for the fact that they have sold lots of it and no one has told them about any problems. All that I can say with certainty is that no medical therapy with any benefits at all is “100% safe,” so this is clearly nothing but marketing hyperbole. Such claims are a hallmark of snake oil therapies.
It is possible, however, to evaluate the claim that RenAvast™ is “scientifically proven.” I’ve talked before about what that means, and it is a good deal more complicated than the promoters of this product seem to understand.
The “research” that the company promotes as evidence RenAvast™ is safe and effective is a classic example of sloppy science used as a marketing tool rather than real scientific research. Information about the study can be found in a summary on the Bio Health Solutions web site and also a more detailed report which was previously made available online by the company and then apparently taken down, but which is available through a web archive.
19 cats with CRF were enrolled in an open ended 2-year study… All cats enrolled were diagnosed by their veterinarians with Chronic Renal Failure. None were on restricted diets. None were receiving fluids. All received 300 milligrams of RenAvast™ two times per day. All had periodic blood work…
There is no information about the cats, how they were selected, how long each was given the product, what other disorders most might have had, or any other details about the population studied or how the study was conducted. It is stated that the cats were enrolled “over a two year period,” but it isn’t clear how long each subject was treated and when or how often bloodwork was measured. Without this information, a huge number of possible errors and confounders could be present.
It is also not clear how the diagnosis of kidney disease was made. Two of the cats appeared to have a urine specific gravity of >1.035, which by the most common standard would not qualify them for a diagnosis of kidney disease. This critical value was not measured in three other cats, all of whom had near normal creatinine levels. This means at least 5/19 (26%) cats cannot be definitively said to even have had kidney disease at the start of the study!
Most cats showed little change in the various parameters measured, though again it isn’t clear how long each subject was followed over the total two-year length of the study. The detailed report indicates that these values were compared from the beginning to the end of the study for each subject. There are specific statistical methods needed to perform such a paired comparison, but no information is available to assess whether or not the methods used were appropriate, so it isn’t possible to say if the statistical tests reported are meaningful.
According to the report, declined or remained unchanged in 17/19 cats. (Of course, this includes the two that probably did not have kidney disease and the three that might or might not have but whose urine specific gravity was not measured at baseline.) Excuses are made for the cats whose creatinine values worsened (one was supposedly not compliant with treatment and the other was receiving medication for thyroid disease which can affect the kidneys). The fact that such possible confounders are not reported for any cats except those whose numbers didn’t change the way the author wanted them do suggests a significant risk of bias in these data. The same pattern is reported for the other variables measured, in which most improve or don’t change and those that get worse are explained away with information not provided for other subjects.
The implication here, of course, is that the failure of these variables to get worse for most cats means the RenAvast™ was working. While this is not a fair conclusion based on the limitations of this single report, the author of the report has no hesitation in making this claim:
These encouraging results prove that AB070597 can halt the advance of chronic renal failure in felines when given as an oral supplement. Supplementation with AB070597 halted increases in blood serum creatinine, blood serum urea nitrogen and blood serum phosphorus concentrations; while at the same time halted decreases in hematocrit and urine specific gravity.
Since cats with renal disease can remain stable for long periods, the fact that there is no control group is a huge problem. It is impossible to say whether or not the product did anything at all without a control group for comparison. In an unusual step, the company has provided some additional information in the form of responses to possible objections to their “study.” It is rare to have the opportunity to see such explicit arguments against what is generally considered appropriate scientific methodology, so I think it worthwhile to examine some of these arguments.
The company FAQ about the study begins by defending the very small sample size.
Many scientific studies are done with fewer subjects and over shorter time periods. In fact, there are thousands of human studies in peer reviewed journals with less than 19 patients. Nineteen patients in a study is acceptable; not to mention the fact that there are numerous over-the-counter medications used to treat humans and animals that are not based on any studies, peer reviewed or otherwise, with only subjective and anecdotal evidence as proof of efficacy.
This seems to me a fallacious argument. The fact that other studies have been done and published with no more subjects than this one isn’t itself a justification for the small sample size. Such studies may or may not have had appropriate samples sizes for the problem and population they studied, but that doesn’t tell us if this number is adequate for this population and problem. Just because others may have also used small sample sizes doesn’t mean doing so is appropriate or that the results are any less unreliable in this case. And there are specific statistical methods for evaluating whether or not a sample is large enough to answer a given question, none of which the company apparently employed in this case.
The argument that many remedies are marketed on the basis of anecdote alone is also not a justification for performing a study that isn’t capable of providing reliable information. Meaningless research is hardly a big improvement over no research at all!
The FAQ then states that biochemistry samples in the study were evaluated at a variety of laboratories. This is presented as a strength, but it may actually be a weakness. Using a variety of laboratories, each with different methods and quality control, introduces a source of variation in the data which can easily alter the findings.
Next, the FAQ attempts to answer perhaps the biggest objection to the so-called study, the absence of any control group. The response rests on two principles. First, it is claimed that a control group was unnecessary because any group not treated would undoubtedly have gotten worse, so any failure to get worse must automatically be due to the treatment:
In this particular case, a separate control group was uncalled for and would not have yielded useful information. The outcome of untreated chronic renal failure is already known: biochemical and hematological blood serum values deteriorate over time.
The problem with this argument is that it is simply false. While the general trend of chronic kidney disease is to worsen over time, the specific changes and the rate at which they happen in any individual are highly variable and unpredictable. Studies routinely show ranges in survival from days to years. Many factors can influence whether bloodwork values worsen and how fast, and none of those factors were accounted for in this study.
And there are many important variables other than bloodwork values, including body condition, appetite, and other clinical symptoms, which are only mentioned in passing but not specifically evaluated in this report.
We don’t even know from the information available whether these cats were properly diagnosed with kidney disease, what stage of disease, or any other relevant prognostic factors. Some of them, at least, clearly were not. And even if these cats all truly had some degree of chronic kidney disease, the progression of the disease over whatever unreported period of time each was followed cannot simply be assumed. Without a control group, no change or failure to change can be ascribed to the treatment in this study.
The second argument presented against a control group is that having such a group would be unethical since untreated cats would certainly die of their disease.
The use of a separate control group often raises questions of unethical behavior regarding withholding treatment from or giving placebos to the control group.
The FAQ then quotes a number of statements from the Stanford Encyclopedia of Philosophy concerning the ethics of placebo controls in clinical trials. It goes on to give an impassioned statement against the use of such controls:
The researcher does not question the superiority of randomized double-blinded studies over other forms. It is a well recognized fact, though, that their use in some situations is completely unethical. The researcher considered it completely unethical to create two groups of cats, both with CRF, and treat one group with RenAvast™ while giving the other group a placebo to merely satisfy statistical correctness. He already knew the outcome of the placebo group…. We fully support the researcher’s decision. We too, find it cruel and unethical to deny cats with CRF treatment with a product that could help them simply to create a statistic.
There are several problems with this argument. The first is that it is inconsistent with the little we know about how this trial was conducted. There is no evidence the cats placed on RenAvast™ were given standard care. Dietary therapy, for example, is well-demonstrated to improve outcomes for cats with kidney disease, yet these cats were not on dietary therapy. Other common therapies are less solidly evidence-based, but there is certainly a basis in plausibility and consensus for the use of fluid and for a number of other therapies depending on the details of the individual cases. The little information we have suggests these treatments were not provided to subjects. This study apparently substituted a completely untested supplement for standard care, which would certainly not be ethical. And if the product is not effective (and there is yet little reason to think it is), this amounted to simply not treating these cats at all, which is exactly what the author of this FAQ decries.
It is recognized practice in clinical research to test new therapies by comparing a group getting standard care plus the new therapy to patients who get only standard care. It would not have been difficult to run this study in this way, ensuring that both groups received accepted diagnosis and treatment and the only difference between them was the addition of RenAvast™ for the test group. This would have potentially provided actual information about the efficacy of this product, which the results reported here do not.
The ethical argument in the FAQ also fails because, as discussed above, the outcome was not actually known in advance as the company suggests. If we could safely assume that an experimental treatment worked before testing it, we wouldn’t need to run clinical trials at all! The reason that placebo controlled trials are ethical is because they are necessary to develop effective treatments. Without them, we simply guess and, as history and the cumulative results of thousands of such trials show, patients suffer from our ignorance. It is certainly not ethical to deny a known effective treatment to patients in a trial. But since RenAvast™ is not a known effective therapy, it is ethically questionable to give it in a clinical trial without having a control group, especially if standard care is not provided as well.
We don’t conduct trials “to create a statistic” or for “statistical correctness” but to generate the real and reliable knowledge that can only come from controlled scientific research. To conduct a trial that doesn’t produce such knowledge but merely facilitates marketing an unproven medical product is where the real ethical failing lies. This is a classic example of circular reasoning, assuming a therapy works before testing it and then claiming it would be unethical to deny this therapy to patients because it works. This is how one does faux science for marketing purposes, not real science designed to generate real growth in our knowledge and therapeutic tools.
The ingredients in RenAvast™ are deliberately not disclosed by the company beyond the fact that they are amino acids and some sort of peptide. Therefore, it is impossible to evaluate the plausibility of the proposed mechanisms of action or any preclinical research on these ingredients.
The only data presented for safety and efficacy is a poor quality, small trial with clear and significant risk of bias that is essentially useless as evidence. There are, of course, plenty of testimonials and anecdotes suggesting the product works, but that is true for every therapy ever invented, so either no idea in medicine ever fails, or anecdotes are very reliable.
There is no way to determine at this point if the product is safe or effective. However, the way that it has been marketed shows a clear disregard for both the regulations intended to prevent inappropriate and unproven claims for dietary supplements and the basic principles of medical research. The combination of secrecy and misuse of sloppy science suggests a great deal of skepticism is in order when dealing with this company and its products.
What Else Do We Know?
In the absence of any real scientific evidence to evaluate the safety and efficacy of RenAvast™, it is impossible to draw any solid conclusion about the product. All we can say is that it is unproven, and even the basic plausibility of the proposed mechanisms is unclear.
While it won’t help us to evaluate the safety and efficacy of RenAvast™, there is some additional information worth considering using this product. As I have already discussed, there are a number of warning signs of snake oil, including claims of perfect safety, dramatic benefits not supported by real scientific evidence, misuse of the appearance of science to market a product, and others. I will not be surprised if we soon see another such sign in the form of a hostile response to this critique, though that is just a guess on my part.
The credentials of the folks making claims for this product are not directly relevant to the truth of those claims, but in the absence of any more specific evidence, they may be of some tangential interest. The detailed report on the cat study is attributed to “James Archer, Photo Research.” There are references elsewhere to a “Dr. James/Jim Archer” associated with Bio Health Solutions, the company marketing RenAvast™, and he has provided a radio interview on a program devoted to “integrative veterinary medicine” discussing RenAvast™.
According to this interview, Dr. Archer apparently invented prior to working with Bio Health Solutions. It is not clear what specific academic or research background Dr. Archer has. He appears to have worked largely for the Department of Defense, and though he is not a veterinarian, he indicates he has been a scientific consultant at a veterinary hospital in Southern California.
In his interview, he repeats many of the assertions for the effects of the ingredients in RenAvast™ without any additional details. He describes extensive research leading up to the development of this product, though apparently none of this has been published. He reports the results of the unpublished study and makes strong claims for the benefits of the product without addressing any of the limitations or problems discussed above. He recommends RenAvast™ be given permanently to all cats over 8 years of age! He does mention that a few of the cats had concurrent diseases or treatments during the study, and he confirms that the avoidance of diets for treatment of kidney disease was deliberate. He also reccommend using the product in dogs as well and mentions that there is research ongoing in this species.
The company web site only lists one other product, another nutritional supplement billed as an analgesic and anti-inflammatory for musculoskeletal diseases in animals. The marketing director, Mark Garrison, describes aggressive marketing of the product around the world. The company claims repeatedly on its web site to have a strong commitment to science, but this certainly is not consistent with the approach so far evinced in promoting RenAvast™.