Have you ever wondered how the ingredients in Renadyl improve kidney health? So have we! That’s why we sat down with Natarajan Ranganathan, Ph.D., the lead scientist and founder of Kibow Biotech, and Dr. Emmanuel Anteyi, the Clinical and Medical director at Kibow Biotech.
We wanted to learn more about how Renadyl was created and what the future holds for probiotic therapy for CKD. In addition, we asked some of the burning questions that we hear from both clients and practitioners alike!
Disclosure: This post is sponsored by Kibow Biotech, the producer of Renadyl, a probiotic for kidney health. As always, all opinions are my own.
A conversation with Natarajan Ranganathan, Ph.D. Founder & Scientist, Kibow Biotech Inc.,
Q. What prompted your interest in researching the gut as a way to reduce uremic toxins in patients with kidney disease?
Answer: It’s so ironic you ask that question. I am from India, the Indian system of Medicine is Ayurveda. Ayurvedic medicine treats all diseases based on the gut. There are three different categories Pitta, Vata, and Kapha. Because my roots are from India, I know that the gut is the origin of all diseases. So the gut is the foundation of all health and disease.
Q. I’m curious how you decided on the ingredients for Renadyl. During the research process was there some trial and error of bacterial strains to determine the most beneficial?
Answer: Kibow was started as a drug development company. Research conducted out of the Jefferson Medical College at the Thomas Jefferson University in Philadelphia found that kidney patients have circulating uremic toxins that can relocate to the bowel where dysbiosis occurs.
Harmful bacteria start competing with the good bacteria, and the bad typically win. They can then move from the large to the small intestines, where they begin seeking nutrients.
By using lactobacillus acidophilus, these researchers showed that uremia was reduced and quality of life improved. That is how we knew that bacteria might help kidney patients.
We asked the question: Can we take the bacteria and clone it with different genes? But this wasn’t easy. We also realized many kidney patients have poor immunity and that using a genetically modified product would not be ideal.
So we started screening different naturally occurring microbes. We started with 150-200 microbes until we settled on three because of their specific properties:
- High capacity to neutralize urea/urease/uric acid/creatinine
- High capacity to neutralize TMAO, methylamine,and dimethylamine
- Ability to reduce indoxyl, p-cresol sulfate
We put all three together and conducted a drug-like validation of the product, for which we have published several research papers.
Q. During patient trials, did you find that Renadyl altered gut motility from the baseline? For example, did those with constipation become more regular?
Answer: As a matter of fact, we have been getting reports from people using Renadyl that their constipation has resolved and their bowel movements are much more regular. However, that was not one of the study outcomes we were looking at during the trials.
Q. How long has Renadyl been on the market? Have there been any reformulations since the original product came out?
Answer: The company was started as a one-person company. For the first two years, I was a synthetic organic chemist. I received a small business innovation research grant that allowed me to set up a lab and bring in microbiologists to start research and development.
We had a hard time getting funding because we were a health supplement company. Fortunately, a Philadelphia-based venture capitalist gave me the idea to sell the product to cats and dogs since they also have kidney disease.
The product took off with the American Holistic Veterinary Association, and we began selling Azodyl for cats and dogs in 2006. We launched the human product, Renadyl in 2010.
The product has not changed since origination, and the dosage for cats and dogs is 15 billion and 45 billion CFU’s for humans. However, we will be conducting a clinical trial because we are the first probiotic company to receive an investigational new drug (IND) from the FDA.
The formulation for the clinical trial will be a slightly modified version from the original. It has the addition of a proprietary strain of bacteria targeted towards removing cardiovascular toxins. This product is geared toward patients with kidney failure because they often have cardiovascular issues.
Q. How long do you recommend that someone with CKD take Renadyl?
Answer: I always tell people that Renadyl is not a drug; it’s a supplement. If you have a specific disease that you take a medication for, you have to take it all the time. Renadyl is meant to be used in conjunction with your standard care of therapy. It helps to remove uremic toxins and makes your quality of life better. This stops the progression of kidney disease.
Some people take Renadyl for only three months. Then when they stop taking it they claim that they do not feel as good and their blood levels are starting to worsen again. When we ask if they stopped taking the product, they say yes. So then we say you should get back to the product and take it as long as you need it.
Q. There are some beliefs that using only one probiotic could lead to an overgrowth of one specific bacterial strain and that it is best to alternate probiotics. What are your thoughts on this theory and does it apply to people with CKD?
Answer: Renadyl has three different strains of probiotics that each target uremic toxins. I don’t believe alternating between one or two probiotics will make any difference. As a matter of fact, most companies are making multistrain probiotics because there are more benefits to using multi-bacterial strains.
We believe that only one or two kinds of probiotics or alternating them will not give as much benefit in comparison to taking multistrain probiotics (like Renadyl).
Q. For people considering taking Renadyl, what would be some of the signs that Renadyl is working for them?
Answer: Most people report feeling more energetic and that their quality of life is improved. I always say that it doesn’t matter what disease you have or what medicine or product you take. Ultimately what is the best way to measure?
When you go to the Doctor, what is their first question? How do you feel? The quality of life is what is most important! In addition, when we look at blood chemistry, almost all blood parameters improve from what they were before taking the product.
Q. Over the last 12 years that Renadyl has been available, can you share a success that stands out to you?
Answer: We have volumes of testimonials of success stories. But at the same time, I don’t claim that any product can have 100% satisfaction for everyone. The benefits of the product are much greater than the risk.
I always say that god willing, this product does become a drug; we won’t have the long list of disclaimers like some of the pharmaceuticals listed on television.
As of now, over the past ten years of marketing the product, we have not had a single report of an adverse event either to us or the US FDA.
That is the main reason that we are the first company the Food and Drug Administration (FDA) has permitted us to bypass phase 2a safety in clinical trials, and we can move directly to phase 2b for Renadyl to be a Live Biotherapeutic Product (LBP).
A discussion with Dr. Emmanuel Anteyi, MD, MBA, MS, FRCP Clinical/Medical Director Kibow Biotech Inc.,
Q. Why are uremic toxins concerning for people with kidney disease?
Answer: When we talk about uremic toxins, we are talking about a wide range of metabolic waste products. For clinical purposes, we classify them into three groups:
- Water-soluble: for example urea
- Protein-bound compounds: for example indoxyl sulfate, p–Cresol Sulfate
- Middle molecules: Beta-2 microglobulin group
Uremic toxins are breakdown products of amino acids in the gut. Uremic toxins are usually excreted and removed by the kidneys, but these waste products accumulate in the body as kidney function deteriorates or declines.
With kidney disease, these waste products can become so high they cause problems in the body. In addition, toxicity symptoms like nausea, vomiting, diarrhea can occur because of the retention of uremic toxins.
Recent research has shown that the retention of uremic toxins can affect many major organ systems. Including the cardiovascular system, the brain, endocrine system and can even cause further progression of kidney disease.
By and large, anytime you have an accumulation of these uremic toxins, you know that there will be a lot of manifestations. But, more importantly, the quality of life decreases.
Q. Individuals with kidney transplants are seeking ways to maintain their kidney function. What are your recommendations for taking Renadyl following a transplant?
Answer: First, let’s look at the situation; having a kidney transplant means you have end-stage kidney disease (ESKD). With ESKD, there is an imbalance of the gut microbiome, which is called dysbiosis. That dysbiosis promotes an altered composition or biodiversity of the microbiome.
Usually, the microbiome eliminates uremic toxins. In a kidney transplant, you replace kidney function with a new kidney that is compatible, but to avoid rejection of the kidney, you have to take certain medications. That is where it becomes tricky, especially with immunosuppressive therapy.
Sometimes people need a lot of antibiotics after a transplant because they can be more prone to infections. Antibiotics can affect the microbiome’s diversity because they can destroy the good bacteria in the gut. Immunosuppressive medications can affect it as well.
That predisposes transplant patients to infections. But on the other hand, if you look at how these probiotics work, they also modulate the immune system. So it’s a balancing act. We tell patients who have had a transplant that it is good to restore the gut microbiota so that you can maintain immune regulation as long as they aren’t taking antibiotics at the same time.
Also, if they are taking high doses of immunosuppressives that might predispose them to infection, we recommend restoring gut microbiome balance. For example, taking specific strains of probiotics known to restore the gut microbiome may prevent infection and help with immune balance.
One major issue with transplants is rejection. Rejection has to do with balancing the immune system, and the microbiome helps maintain that balance. So we say that yes, probiotics can be used as long as there is no contraindication at that particular time.
Q. There are a lot of conflicting thoughts about utilizing probiotics for people with certain conditions. For example, small intestinal bacterial overgrowith (SIBO), and even catheter use have come up as a concern. Are there any circumstances when Renadyl is not recommended?
Answer: Probiotics are classified by the FDA as generally regarded as safe (GRAS). In terms of disease conditions, we advise people to be careful with active infections or active disease of the bowel. In addition, people who have had surgery in the GI tract because of the site of action of probiotics in the colon will also want to be very careful. If there is an active bowel disease, we recommend avoiding them or using them very carefully.
We also advise people to be careful if they take Vitamin K-dependent anti-coagulation medications like Warfarin/Coumadin. Because the strains of probiotics in Renadyl produce Vitamin K, it can interfere with the action of these medications.
We advise that patients switch if possible to anti-coagulation medication that is not Vitamin K dependent if they want to take Renadyl. Eliquis is one of the anticoagulants that are not Vitamin K dependent.
Q. Are there any other medication contraindications with Renadyl?
Answer: Yes, especially antibiotics. When taking antibiotics, we recommend waiting to take Renadyl for at least 3-4 hours after taking the antibiotic. Or, since antibiotics are usually dosed for a short period of time, they can pause taking probiotics until they have finished their course and resume their probiotic therapy.
Prednisone is a steroid medication that can suppress the immune system and is used in many clinical conditions. As long as the prednisone dosage is no more than 10 mg/day, it is likely safe for renal conditions. However, you have to weigh the risk to benefits with high doses.
Steroids are often used to modulate the immune system to treat the disease condition. Therefore, providers need to weigh the risk to benefit when recommending probiotics for patients receiving high doses of prednisone.
One has to be very careful because probiotics are live microorganisms, and the risk of infection is there even though it is low. The microorganisms in Renadyl are beneficial, but there is a risk for translocation (bacteria getting into the bloodstream), especially in people that are immunosuppressed when using high doses of prednisone.
Maintenance doses of steroids are typically very low, which should be ok for most people. However, for people in the high dose or induction phase of steroid therapy, you have to be very careful again.
Q. Are there any specific types of foods or prebiotic fibers that can help to feed the bacteria found in Renadyl?
Answer: Probiotics alone don’t do a lot. But, if you add dietary fiber, you increase the diversity and the composition of the properties in the gut. Besides that, dietary fiber also produces short-chain fatty acids, which are responsible for the integrity of the gut and epithelial lining.
Short-chain fatty acids also promote certain metabolites that prohibit the growth of pathogenic bacteria, which contributes to immune regulation.
Dietary fiber also helps control appetite, which we know is involved with obesity. In addition, dietary fiber or prebiotics have a laxative effect or bulking effect. That’s why it’s good to include the two types of prebiotic fiber: soluble and insoluble fiber.
The soluble fibers are fermentable and are associated with the production of short-chain fatty acids, regulation of the immune system, and control of metabolic processes. The insoluble ones are also good for laxative effects, bowel movement, and bowel cleansing. So when selecting dietary fiber, it’s good to have a mix to have these two effects.
Future research
Q. What do you think the future of probiotic therapy will look like?
Answer: The field of probiotics is evolving. For the last decade or two, we have had more understanding of the various strains and phyla of microbiota. Now, we’re discovering that the field of probiotics is not one size fits all.
We are now finding out that probiotic therapy depends on the disease condition people are dealing with. And so the tendency now is to look at a particular area which people can concentrate on. To do so, we have to identify the strains that will be beneficial in certain disease conditions because the strains that are beneficial in chronic kidney disease may not be the same strains that will help people dealing with chronic diarrhea or gut health.
At Kibow, our focus has mainly been on kidney health. So the research that has been done over the years is to identify specific strains of these organisms that are beneficial in restoring kidney health.
For the past decade or so, we have been very sure about three very beneficial strains for people with kidney disease. Specifically, these strains are the streptococcal thermophilus and lactobacillus groups because they have specific urease activity, which breaks down the urea and eliminates most uremic toxins.
We are now going into the era of personalized individual formulations that will deal with specific diseases.
Of course, we are always looking at how to improve our formulation. We are now carrying out a clinical trial on one of our formulations. The idea is to look at various combinations for different disease conditions within the CKD spectrum, like dialysis patients and pediatric chronic kidney disease.
And so at Kibow, what we try to keep doing is looking at the strains and species of the bacteria beneficial to kidney health and the multifiber combination that helps to promote the growth of those bacteria so that they work in synergy between the multifiber and the multistrain.
What we’re aiming to do is to provide a broad spectrum of products for the CKD population, including predialysis, dialysis, and, of course, even transplant because the next phase, once we’re able to go through the CKD stage and dialysis stage, the next group we’ll focus on is transplant and even peritoneal dialysis.
As of now, we are trying to design a study for peritoneal dialysis and post-transplant, but we are still trying to finish up with our CKD, dialysis, and pediatric CKD studies.
Q. Are you considering any studies or clinical trials in the near future?
Answer: We are currently doing a clinical trial on an FDA-approved test drug for a biotherapeutic product formulated by Kibow to evaluate the safety and efficacy of patients with chronic kidney disease stage four.
Why stage four? We know there is an unmet need for intervention at stage four, and people are hanging onto the cliff, more or less than any other stage in the CKD spectrum.
And we also see that there’s a void in the therapy of individuals in this group. Most of the treatment we have currently targets the progression of chronic kidney disease, usually in the early stages of chronic kidney disease, stage one to stage three.
Once they are in stage four, most people feel that they have no other option than to prepare for dialysis. However, for most people, if you ask them whether they want dialysis or not, it’s likely, you would not get a positive response from even one because nobody wants to have to go on dialysis. There are some people who are not suitable for dialysis for different reasons.
That’s why we are looking at this CKD stage four group to see if we can halt the progression or retard the progression of CKD or even delay the need for dialysis in this population.
So what we are doing now is going through the FDA-approved Phase 2b clinical trial to evaluate the safety and efficacy, and we are looking at 630 patients in about 20 sites in the US.
We have already activated about 15 sites and started enrolling patients in October (2021). I would hope that we should have preliminary data by April or May (2022). After that, patients in the placebo group will roll over to an open-label six-month trial.
From this data, we’ll see the safety and efficacy, and we should be able to plan for the larger phase three clinical trial, which will be multi-site in and outside the United States because it would require about 1000 plus patients in that group.
We will potentially register for a new drug application if we achieve our primary endpoints. This would make the new drug available to most people in the United States and other parts of the world with a prescription.
Studies in the dialysis population
This study’s target population is dialysis patients, and the formula includes about five bacterial strains with multifunctional fiber. And the whole idea here is that we want to see if we can reduce uremic toxins. These are the toxins that we discussed earlier on.
We have found that most dialysis patients die not because of primary kidney disease. Instead, 60% of them died because of cardiovascular complications. Most of this can be attributed to uremic toxins, especially Indoxyl sulfate, PCS, and TMAO. Unfortunately, dialysis cannot clear these toxins because they are protein-bound.
So even the best dialysis currently can only remove about 30%. But both animal and human studies have shown that this combination of probiotics drastically reduces the uremic toxins, so we should think that quality of life will be better, mortality and morbidity should decrease, and there should be an improvement in dialysis adequacy.
In addition, pediatric CKD clinical trials should also start later in the year. Children are a very vulnerable group, so it is challenging to get approval for the pediatric population. So usually, we’ll look at it in adults, and then we can formulate the dosage and then test on children.
That’s why we’re waiting on the data from the adult study before moving on to the pediatric group. As you can see, our hands are full!
Thank you Kibow Pharmaceuticals for your work and passion for the kidney community!
I’m Jessica, one of the renal dietitians at the Kidney Nutrition Institute. As a renal dietitian, helping patients live well and thrive through nutrition and lifestyle changes is near and dear to my heart. That is why I am so grateful to have had the opportunity to talk with Dr. Ranganathan and Dr. Anteyi!
Kibow Biotech is a pioneering company that looks at kidney care through a different lens. They see the big picture of CKD; targeting kidney disease from a holistic approach can help patients live well. Here are some of my favorite takeaways from my interview with the founder and medical director.
- Renadyl was born from the Ayurvedic principle that disease originates in the gut
- Not one person in over twelve years has reported an adverse event- this speaks into how integral gut health is to kidney health
- There are some circumstances in which practitioners should use their best clinical judgement when recommending Renadyl
- Probiotic therapy is a rapidly evolving science and finding pre and probiotic strains for specific diseases and conditions is the future
- Kibow Biotech is only at the tip of the iceberg when it comes to developing producs that will positively impact the kidney community
I can’t wait to see what innovative kidney care solutions Kibow Biotech comes up with next!
Visit Kibow Biotech to stay up to date on the progress of the clinical trial and new products and services.
