Archive October 2018

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How Afatinib Changed Our Everyday Lives This Summer

How Afatinib Changed Our Everyday Lives This Summer

Home and Family > Hobbies | By: Elias Byskov (29-Oct-2018 22:23) Views: 2
Examination exposed modest distress as a consequence of discomfort, designated ache in any passive or active combined motion inside feet, knee, and also stylish joint parts. Examination of your important joints must be aborted as affected person rejected for you to interact personally because of the discomfort. Nerve evaluation exposed zero obvious sensory or perhaps generator failures. Individual had been presently taking tacrolimus (3?mg inside morning and a couple of.5?mg inside evening) together with prednisone use in dogs 5?mg daily because immunosuppressive remedy. Along with cystic fibrosis, he also experienced pancreatic deficiency, type 2 diabetes, renal lack, gastroparesis, blood pressure, depressive disorders, along with sinusitis. Your laboratory info revealed an ordinary tacrolimus trough degree of 12.4?ng/ml (5-20?ng/ml). An extensive attempt to assess pain regarding rheumatologic ailments, porphyria, along with neuropathy was undetermined. Radiographs https://www.selleckchem.com/products/z-vad-fmk.html with the concerned bones had been normal. Your navicular bone scintigraphy check out confirmed greater tracer uptake bilaterally from the rearfoot, leg (together with tibial base), stylish joints, as well as make (Fig.?1a). Your permanent magnetic resonance image resolution (MRI) with the bilateral sides as well as shins unveiled marrow edema that’s stretching out to the base with the femora (Fig.?1b and also d). Any triad involving unremarkable radiographs, elevated customer base on bone scintigraphy, along with navicular bone marrow edema about MRI supported detecting CIPS. Along with the encouraging attention, selleck discomfort manage, the actual serving with the tacrolimus was lowered on the half of his or her current serving and also amlodipine 5?mg has also been started. This triggered the actual speedy improvement in their signs or symptoms. Their replicate tacrolimus level ended up being Several.8?ng/ml right after Afatinib halting tacrolimus. Within just 3?months, this individual could ambulate without the pain or perhaps recurring incapacity. To sum up, CIPS is often a unusual entity taking place in 1% involving reliable wood transplant people [5]. Lucas et?al. [4] referred to a new musculoskeletal ache malady the first time following the introduction of calcineurin inhibitor treatments which faded following the stopping of cyclosporine throughout kidney hair treatment people. This specific discomfort malady continued to be uncharacterized till Grotz et?al. [5] outlined these standard radiological symptoms: (we) regular preliminary radiograph, (two) improved tracer uptake around the navicular bone scintigraphy, and (3) bone fragments marrow edema in MRI leading to conceptualization of CIPS. All three of these findings ended up seen in the person explained the following. Soreness throughout CIPS is usually symmetrical without having pores and skin adjustments, episodic, and also self-limiting. CIPS is actually comparatively which is related to CIs. Each of our affected individual developed avascular necrosis associated with his or her bilateral hip bones extra to the extended corticosteroid remedy; however, concurrently he had signs or symptoms impacting on additional bones along with radiological studies to aid the diagnosis of CIPS. The particular onset of CIPS will be adjustable. It’s been n around 3?days following the iv infusion associated with cyclosporine [7] so when late while 8?years, because noticed in our affected person. About the Author Elias Byskov It may well appear as if Z-VAD-FMK,Galunisertib,Afatinib is a matter that is definitely hard to master, but it really is not that hard to discover when you give it an honest try. Anyone that attempts something for the first time might perceive that the activity is usually challenging first time around. After you have found out what to do, you can actually take command involving any predicament. All that’s necessary will be the correct background, and also the ability to complete it effectively. It is straightforward to get much more info, and keep on your journey, when you go to learn more right now. Everyone that goes to Afatinib is able to locate strategies as well as strategies which will be highly helpful for you. Popular Tags

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Methotrexate folic acid for RA: Managing side effects

<h1>Methotrexate folic acid for RA: Managing side effects</h1>

Methotrexate folic acid for RA: Managing side effects

Table of contents How does methotrexate affect folic acid? Ways to reduce side effects Other side effects and risks Seeing a doctor Outlook Methotrexate is a medication that doctors prescribe to treat certain conditions, including adult rheumatoid arthritis, some cancers, and severe psoriasis. However, methotrexate drains the body of folic acid , which may lead to folic acid deficiencies.
The body needs folic acid to maintain a healthy gastrointestinal (GI) tract and liver, as well as healthy bones and hair.
Methotrexate can also cause side effects, such as nausea, vomiting, and stomach pain. A person taking the medication for rheumatoid arthritis (RA) can take a folic acid supplement to help reduce these unwanted side effects.
In this article, learn more about how methotrexate affects folic acid, as well as about the other possible side effects.
How does methotrexate affect folic acid?
Methotrexate can treat a range of conditions, including RA. Folic acid is a B vitamin . An enzyme in the liver converts folic acid into folate , which plays many essential roles in the body, including helping with cell division and DNA replication.
Methotrexate works by reducing the amount of folic acid in the body, which means that harmful cells cannot replicate. This is the reason why some people with cancer take the medication.
Doctors do not know exactly how methotrexate works to reduce RA symptoms.
However, according to the U.S. Food and Drug Administration (FDA) drug information document, methotrexate might affect immune system function, reducing the body’s immune response that causes RA symptoms.
The FDA information document also notes that methotrexate can reduce swelling, inflammation , and tenderness caused by RA within 3 to 6 weeks of starting to take the medication.
Because methotrexate also depletes folic acid levels, it can cause a variety of side effects, including, mouth ulcers, headaches , and fatigue . Taking a folic acid supplement can reduce the risk of these side effects.
Taking a folic acid supplement does not seem to change methotrexate’s effectiveness in treating RA.
Ways to reduce side effects A doctor will make recommendations on how much folic acid to take and when to take it.
According to the Arthritis Foundation , some doctors suggest taking 1 milligram (mg) of folic acid a day. Other doctors may recommend taking a single 5-mg dose weekly.
Some people will take the folic acid supplement 24 hours after taking a methotrexate dose.
In a multi-study review of placebo-controlled clinical trials on the effects of folic acid supplementation, the authors made several conclusions:
GI side effects : Folic acid reduced the risk of methotrexate side effects, such as nausea, vomiting, and stomach pain by 26 percent. Liver enzymes : Taking methotrexate can increase liver enzymes, which could be toxic to the liver. The study showed that taking folic acid can reduce a person’s relative risk of developing liver enzyme problems by 76.9 percent compared to someone who didn’t take it. Mouth sores : The authors did not find a statistically significant reduction in mouth sores when a person took folic acid. Also, the researchers did not find a link between taking folic acid and the effectiveness of methotrexate for treating RA.
In addition to taking folic acid supplements, a person can also reduce the side effects of methotrexate by:
Talking to a doctor about dosage . Some people who take methotrexate may experience fewer digestive problems if they take half the dose in the morning and a half at night, both with food. Considering switching to an injectable medication . Sometimes, injectable methotrexate causes fewer GI side effects than the tablet does. Asking a doctor about anti-nausea medications . Taking anti-nausea medications, such as ondansetron (Zofran) may help reduce methotrexate-related side effects. Using mouth rinses to reduce sores . Doctors may sometimes prescribe special mouthwashes or a person may choose to use a warm saltwater rinse. A person can also ask their doctor about other ways to reduce methotrexate-related side effects.
Can vitamin D relieve joint pain? Vitamin D is essential for bone health, but can it relieve the symptoms of arthritis? We look at the research. Read now Other side effects and risks Pregnant women should not take methotrexate because of the potential risks that a folic acid deficiency and other side effects can have on a developing fetus.
Those with alcohol use disorder should also avoid methotrexate because it increases liver enzymes and can be toxic to the liver.
Other side effects that can occur as a result of taking methotrexate include:
anemia , or low red blood cell counts changes in mood gastrointestinal bleeding headaches increased risk for stress fractures leukopenia, or low white blood cell counts non-productive dry cough pancreatitis rashes trouble thinking clearly It is a good idea to discuss possible side effects with a doctor before taking methotrexate.
When to call a doctor
A person should call a doctor if they experience side effects, such as fever, A person should call a doctor right away if they experience any of the following side effects:
bleeding dehydration diarrhea fever mouth sores shortness of breath skin rash While some of these side effects are relatively widespread among people who take methotrexate, anyone experiencing them should let their doctor know. A doctor can recommend other interventions for these side effects.
If anyone experiences severe side effects, such as bleeding, they may require hospitalization to check blood levels and for other treatments.
Outlook While methotrexate can help treat RA, it can lead to folate deficiency and cause other side effects, such as an upset stomach .
Taking a folic acid supplement can help reduce some of these side effects.
People should talk to a doctor about how much folic acid to take and when to take it for RA.
Related coverage How can I sleep with rheumatoid arthritis? Rheumatoid arthritis (RA) is a disorder that affects the immune system and may cause joint stiffness or pain. RA may make sleep difficult, and a lack of sleep may make the condition worse. There are many tips for improving sleep including avoiding caffeine and alcohol. Learn more about how to sleep better with RA here. Read now Best exercises for rheumatoid arthritis pain People with rheumatoid arthritis (RA) can benefit greatly from developing a daily exercise routine. Certain exercises can reduce RA pain, improve joint stiffness, and increase range of motion. In this article, we discuss the best types of exercise for RA, along with general exercise tips, and which exercises to avoid. Read now How to deal with prednisone withdrawal Prednisone is a drug that contains synthetic cortisol. When a person takes prednisone, the body stops making enough cortisol on its own. This can lead to withdrawal symptoms when the person stops taking the medication or reduces their dose too quickly. Here, learn more about the symptoms and how to prevent them. Read now Can apple cider vinegar help with arthritis? Some people find that apple cider vinegar improves the symptoms of arthritis, including swelling, pain, and inflammation. But does it work, and is it safe? In this article, we look at the link between apple cider vinegar and arthritis, safety, and alternative home remedies, including cherry juice. Read now Tips for dealing with rheumatoid arthritis flare-ups Rheumatoid arthritis (RA) flares come and go in waves. When an RA flare occurs, people can use a range of methods, including medications and lifestyle changes, to help manage the symptoms of inflammation. Symptoms include joint pain and stiffness. In this article, we look at effective ways of dealing with RA flares. Rheumatoid Arthritis Pharmacy / Pharmacist Additional information Article last reviewed by Mon 29 October 2018.
Visit our Rheumatoid Arthritis Rheumatoid Arthritis.
Dhir, V., Sandhu, A., Kaur, J., Pinto, B., Kumar, P., Kaur, P., … Sharma, S. (2015, June 11). Comparison of two different folic acid doses with methotrexate — a randomized controlled trial (FOLVARI Study). Arthritis Research & Therapy , 17 , 156. Retrieved from https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-015-0668-4
Gower, T. (n.d.). Methotrexate: Managing side effects. Retrieved from https://www.arthritis.org/living-with-arthritis/treatments/medication/drug-types/disease-modifying-drugs/methotrexate-side-effects.php
Methotrexate tablets, USP. (n.d.). Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008085s066lbl.pdf
Shea, B., Swinden, M. V., Tanjong Ghogomu, E., Ortiz, Z., Katchamart, W., Rader, T., … Tugwell, P. (2013, May 31). Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews , 2013 (5). Retrieved from https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD000951.pub2/full
Nall, Rachel. “Methotrexate and folic acid for rheumatoid arthritis.” 29 Oct. 2018. Web.
29 Oct. 2018.
APA
Nall, R. (2018, October 29). “Methotrexate and folic acid for rheumatoid arthritis.” Medical News Today . Retrieved from
https://www.medicalnewstoday.com/articles/323500.php .
Please note: If no author information is provided, the source is cited instead.
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IPF Remedies Helping, But Urgently Need Help for Pulmonary Arterial Hypertension

<h1>IPF Remedies Helping, But Urgently Need Help for Pulmonary Arterial Hypertension</h1>

IPF Remedies Helping, But Urgently Need Help for Pulmonary Arterial Hypertension

Cure Pulmonary Fibrosis: Lung Disease Natural Remedies Oil Pulling Jimmy (Dallas, Texas) on 05/17/2008
I have pulmonary fibrosis a lung disease that HAS no cure.Yet, since I have been on Sunflower Oil (cold pressed & Unrefined) my lungs within 4 days begain to have a healing effect that even the Doctor’s don’t quite understand?! What this oil is doing for my Lungs is or has brought back my Breathing as I have never expected. I had Cancer in my right lung and this oil has completely healed it completely… Amen! If you are interested in the healing of your lungs… please go to the health store and purchase one (1) bottle of this oil and place it within your mouth and swish it around until it turns white; spit it out and then brush your teeth and wash your mouth with tooth paste… As well look on the Net for: “Oil Pulling Cure” and learn what it will do for you… Jimmy.
EC : Read all about Oil Pulling here: http://www.earthclinic.com/remedies/oil_pulling.html Ottawa, Ontario Canada 05/31/2008
Are there any updates to Jimmy from Dallas re Pulmonary Fibrosis article? I have the same condition, but there is very little user experiences articles to read. Gurgaon, India 02/21/2012
Any news from Jimmy of Dallas Texas ? How are you? My husband has pulmonary fibrosis. Have you tried serrapeptase too? Has oil pulling helped you? How are you now? Miller, Sd 08/11/2012
Any news from Jimmy of Dallas Texas ? How are you? My father has pulmonary fibrosis. Have you tried serrapeptase too? Has oil pulling helped you? How are you now? Pulmonary Calcification Posted by Sweetdevilwitch (Bandar Seri Begawan, Brunei Darussalam) on 05/17/2011
Good day to you. How are you? I have my yearly x-ray last march, and the result were alarming I got a small pulmonary calcification but on my x-ray last year I dont have any problem. What should I do to get rid this calcification? Arhus, Denmark 06/10/2013
I red in in a book (Maria La Justicia Bergasa, she is from Spain) that some people got cure from pulmonary calcification using magnesium chloride. Pulmonary Fibrosis Remedies Posted by Kk (Delhi, India) on 06/13/2014
My mother has been diagnosed with Pulmonary Edema and Pulmonary Fibrosis. After extensive search, I reached this website and there seems to be a ray of hope. I saw posts from a few like Jimmy Vou and Maureen who have benefited from the alternative treatments. And my questions is related to that only.
My mother has been prescribed NAC-600 (twice a day), Sildenafil (thrice a day) and Diuretic (twice a day). I would like to know if:
1. Aloe Vera Juice, Apple Cider Vinegar and H2O2 treatment can be given in addition to the on going allopathic treatment or not.
2. Can Aloe Vera juice and Apple Cider Vinegar be mixed together and given at one go or need to be given separately.
3. My mother is also experiencing Diarrhea, so will Aloe Vera cause problems as this is considered to act as laxative and may increase this Diarrhea problem.
4. Is Aloe Vera juice what should be given or is it Aloe Vera Oil?
5. As Apple Cider Vinegar acts as diuretic itself, so will it cause problems for my mother as she is already prescribed a diuretic.
If someone can help me with these queries I will appreciate that.
Thanks, Lakhwant 2115 posts
Kk: Herbs that help kidney function are Cranberry, Parsley, and Slippery Elm.
As for the p fibrosis, the common antibiotic Doxycycline is effective. How the Doxy reacts w/ the other meds I don’t know, check w/ doctor or pharmacist.
The product “PainRx” is an herbal extract that reduces inflammation which is a leading factor in progressive fibrosis. Replied by Dr Balkrishna Narayan Apte Currently Al Khafji, Saudi Araia. Permanant Mumbai 11/20/2016
When you say you take NAC 600, is it 600 micrograms or milligrams? Is it taken once a day or two or three times a day and when – morning, afternoon or at night? Is it taken after meals and with a sip of water?
I am sorry to ask you so many questions. Please forgive me.
Dr Bal Apte Reply Posted by Octavio (Los Angeles) on 10/07/2013
Hello everybody, first of all I would like to thank everymember on this site for sharing their experiences and situations, and recommendations, this definatelly helps other users to have a better understanding about their ilnesses.
My dad suffers from pulmonary fibrosis since 2010, it seems like every time situations gets worse, he gets tired easily, and constantly has to be on artificial oxygen.
After reading posts about similar situations on this site, I saw that many users are relying on aloe vera oil juice and apple cider vinegar, I definitely think this will help improve my dad’s health, I just want to know what would be the ideal portions of this two products and what would be the right amount of times to drink it. Please anyone am waiting for an advice, … Replied by Mama To Many Tennessee, Usa 10/07/2013
Dear Octavio,
I am so sorry about your father’s suffering. And it is hard to watch our parents suffer. He is blessed to have you wanting to help him!
Apple Cider Vinegar is a good thing to try. Safe and inexpensive. Try to find raw and unpastuerized. Start him on 1 teapsoon per day in a glass of water. The next week, try 2 teaspoons per day. The next week, try 3 teaspoons per day. Times of day aren’t critical–one glass in the morning and one in the evening. I just sip on my vinegar water throughout the day.
I am hoping someone else knows about dosing the Aloe, I don’t have much experience with that.
Do some research on this site about Hydrogen Peroxide Inhalation therapy. It helps get oxygen to the lungs and helps with healing. We have used this for my asthmatic daughter with success.
I also bought an essential oil nebulizer for my daughter with an essential oil blend called “Lung Healing. ” It has helped her a lot. I highly recommend it, though a diffuser is not cheap.
I get the oil blend here:
If you have a way to make him fresh carrot juice, that would be really good for him.
Please keep us posted on how things work for him.
~Mama to Many~ Reply Posted by Joseph (West Bloomfield, Mi) on 07/09/2013
My name is Joseph and I am in search a cure for Pulmonary Fibrosis my Mother was diagnosed with it a few years ago. I am hoping and praying that Hydrogen Peroxide works. I also have a comment too about Beet Juice- it cures high blood pressure, Dr. Oz said so on his show about a month ago or so. May God bless you all! If anyone has actual evidence for healing Pulmonary Fibrosis please contact me.Thank you. Philly, Pa 07/10/2013
Hello, it is my understanding that iodine deficiency is fairly common in western developed nations, especially since the bread and baked goods industry stopped using it as a dough conditioner in the 1980s replacing it with bromine, and since the dairy industry stopped using it for teat dip, again replacing it with bromine. Also the low salt craze means people are not eating enough iodized salt anymore (processed foods are not required to use iodized salt, you have to go out of your way to buy it and use it at home). Further compounding the issue is the use of chlorine to sanitize municiple water (which is cheaper but much less healthful than using ozone or ultraviolet light) and fluoride to treat tooth decay (questionable benefits, multiple harms). Long story short, these halides displace iodine, even though iodine is needed by your thyroid and every other tissue in your body. Iodine serves hundreds of necessary functions in the body and one of these is to prevent cancer and fibroids. I cannot recommend your mother take iodine if she is already on thyroid hormones: You will need the help of a qualified holistic dr which I highly recommend in all cases. If she is not on thyroid hormones you could get her to try kelp tablets which have iodine, selenium, and other trace minerals from the sea. I personally use lugols 2% iodine (amazon) as a preventative measure with selenium tablets 200mcg (super fresh). Uniontown, Oh 07/10/2013
Hi Joseph, I have seen these two supplements mentioned in regard to Pulmonary fibrosis but have no experience in this treatment. One of them is also thought to lower blood pressure. This may be of interest for your Mother: http://www.inflammation-systemicenzymes.com/pulmonary-fibrosis.html?start=1
Best wishes. Islamabad 07/03/2015
Anyone want to get rid of IPF (Idiopathic Fibrosis of lungs), please try homeopathic medicine….Nitrium Phos 200. Take this medicine everyday and be happy and trust in God. Please try to be happy all the time. Worries only add to the disease. Florida 01/13/2017
Where do I get Nitrium Phosphate 200? My husband has PF and Dr’s have suggested Palliative care. I don’t want to give up on him!
Stacey, Amazon and 1 800 homeopathey are some sources.
Although I would read through Teds remedies here on Earth Clinic.
He is spot on with his remedies.
Janet Montreal 06/18/2017
Hello, a year ago I joined my husband in Montreal. I was never diagonised in Pakistan but in Montreal I have been diagonised with moderate IPF(lungs fibrosis) The homeo medicine you mentioned is to cure slowdown or simply help breathing and is it available in pakistan? plz reply thanks Reply Posted by Nikul (Mumbai, Maharashtra) on 04/29/2013
Dear Ted, My Mom has been diagnosed with pulmonary fibrosis 1.5 years ago. She has been taking Pirfenex and other medicines along with natural supplements.
She is on 5Ltr oxygen concentrator 24 hour with Bipap machine and can only maintain 70% of her oxygen when she is walking… When she is quiet it goes up to 87%… She coughs a lot and she is very exhausted when she does her sputum is very sticky and stuck somewhere in throat. Battleground, Wash 04/30/2013
Please read Dr. Batmanghelidj book called ABC OF ASTHMA ALLERGIES & LUPUS. He has some very wonderful information on how the body works and how to maximise your health even if you are dying, come back to life. Water, salt, minerals, nutrients in the right proportions and at the right time for the body to be optimum health.. hope you get to have your mother for years to come … Faridabad 05/11/2015
Hi Nikul, if you can share your contact details please. My mother is also an IPF patient. We can share the valuable information. Pulmonary Fibrosis Treatment Posted by Lalit (Mumbai, Maharashtra , India) on 06/07/2013
Dear All, Pls help me with providing the permenant cure for the Lungs fibrosis, my mother is suffering from this and every day the pain she has to bear is not possible to see. SO pls is any one is having the permanent cure pls contact with me on : 917350501500. Lalit Diane (Pa) on 02/23/2017
Four years ago I was diagnosed with Pulmonary Fibrosis. One 120,000 units (enteric-coated) serrapeptase (can do this three times daily – must be taken on an empty stomach) and one or two – 600 NAC (taken with vitamin C) does wonders for me. Haven’t had an MRI or CT-scan since the initial one. My pulmonary doctor wanted me to have a lung biopsy (to try to figure out what caused it), but that didn’t appeal to me. All the scars from working in the deli (friers) have disappeared though, as well as ALL the other scars that I had collected throughout my life-time. Serrapeptase eats away the scar tissue (as well as blockages in arteries), and the NAC thins out any mucus. I’m still here, so something must be working. East China, Michigan 03/21/2017
I have just started my serra and nac useage about two weeks now, how did you determine the dosage you need to take? Any info will be greatly appreciated. Pa 03/22/2017
Honestly, I just go by how I feel, what the labels tell me I can take, but I did it religiously for about the first 6 -12 months. I’ve read that some people feel better taking 40,000 units rather than the 120,000.
I did neglect to mention that I also take magnesium and vitamin d daily. Sometimes magnesium citrate, and sometimes a brand that says that it’s high absorption magnesium, 100% chelated.
I never took lungs formulas or other systemic enzymes, like I read that others do when I was researching about it, and I personally would avoid taking anything with nattokinese, because it doesn’t know when to stop lysing.
Father(NONsmoker) w/ lung trouble many years. No blood but cough uncontrollably, too much to bear.
Got Exposed to black mold in the house he was in. Coughing worse, very severe!
Were you ALSO exposed to MOLD infection? His lungs show 2/3rd black&dead.
How homeopathically cleanse body of mold, will Serrapeptase&NAC, etc. take care of this??? Mucus he coughs-up is clear…
Can you shed any more light on this? You seem to have won your battle.whew
Was there ever a mold connection for you? Thank You, and congratulations!! Quebec 05/24/2017
Hi. Sounds very encouraging. I just bought neprinol and NAC. Pray it helps my very scarred lungs due to scleroderma. Hope your still doing well. How many did you commence with? Blessings and thank you! 06/07/2017
Marla,
When I was first told I had pulmonary fibrosis, I checked Neprinol, but it was not in my budget. HOWEVER, I came across a review on Amazon about it, and the person said he or she started out with 3 a day in the comments section under their review. I just looked at it again, and you should be able to easily find that review with the title “very interesting product”. All the best to you. Pa 06/07/2017
I don’t know about a mold “connection” causing my PF. It could have been any number of things… But since I didn’t get into all that with the pulmonary doctor after she told me she wanted me to have surgery for another issue that she was concerned with, in addition to the lung biopsy, there’s no way for me to know. I used to cough uncontrollably also.
Will the Serrapeptase and NAC take care of it? I don’t know, but the alternative is well, not good.
All I know is that there was a package for Pulmonary Fibrosis that I could not afford, so I’ve done what I can with the money that I have. I’ve tried to figure out what would be similar, as they used serrapeptase, a formula that I think had serrapeptase and nattokinese, and some other things. The closest enzyme I could find that had the other things, I found in a enzyme formula, and since we are not allowed to name a specific formula, the ingredients in it are pancreatin, protease, amylase, lipase, bromelain, rutin, papin, serrapeptase, trypsin/chymotrypsin complex, trypsin, chymotrypsin, amla fruit.
In a few months, when I can afford it, I may add that formula to my aresenal.
And then, I’ve used the NAC, but alternated it with mucolyxir (microdose dna). I think the objective is to get the mucus out.
I used to wheeze so loudly that I had a hard time going to sleep, and although I’m sure I wheezed throughout the day, as soon as my head hit the pillow. So that’s improved, because I hardly notice it anymore.
See, I was diagnosed with asthma about a year before the other diagnosis. My doctor wanted me checked for asthma because I was coughing a lot, and it took a month for me to get the pulmonary function test. The woman who did it suggested I tell my doctor my lips were blue that day. So, who knows which came first, the chicken, or the egg (the asthma, or the pulmonary fibrosis?
I also do read healing scriptures, Psalms 103:1-4, Isaiah 53:1-6, Psalm 118:17, and all the healing that Jesus did in Matthew, Mark, Luke, and John. I don’t see where He refused to heal anyone that came to Him. Galax, Va 06/09/2017
My friend has idiopathic pulmonary fibrosis. He noted that many of the patients at the clinic he goes to, many WWII pilots or crew, were exposed to fine oil particles in the cockpit during missions–everything was covered in oil when they would get back. He feels this is the cause of his disease. Durban South Africa 06/19/2017
Hi Diane my father has been diagnosed with Ipf n I’ve started him on serreptase for one week now he take 30mg a day after how long did u c results n what is NAC? I want to understand his condition therefore researching n speaking to people with his condition Many thanks 2 posts
Hi
My mother is diagnosed with Idiopathic Pulmonary Fibrosis in 2014 and under taking medication as per pulmonologist advice (in India). 10 different medicines, including Pirfiner (200 mg) thrice a day
After recent visit to the clinic and disease progression, clinicians indicated maximum survival of 1 year. My mother is under 16 hours of Oxygen support at home.
I had come across Earth Clinic through google, and read positive reviews from people affected by PF, but not very clear about the dosages and combination of alternative medicines they are taking. Will it be possible to arrest the disease progression, by taking serrapeptase (enzyme) and Hydrogen peroxide. However I am not sure how to get these alternative medicine in India. Does anyone know where to buy them to ship to India? Can anyone advice the dosage for these medicines.
2. Can we take these medication along with other medication given by Pulmonologist?
Looking forward to hear from you at the earliest
Sivakumar S 07/22/2017
Diane,
Thank you for your posts. Would you explain why nattokinase “doesn’t know when to stop lysing” from your 3/22 post? And why is serrapeptase different from nattokinase? I tried to find the info in the internet, but couldn’t. Thank you. 08/11/2017
That is amazing news Dianne,
When is your next MRI or CT Scan? Would love to hear whether the enzymes have made any structural differences and how your lung function is? Do you feel the enzymes are working effectively over time and what has your doctor said about you condition since supplementation? Also what conventional treatments are you currently on? I’m worried the enzymes would interfere with the immunosuppressants I’m on or heart meds like blood thinners and blood pressure tabs? Would you know where I can find more guidance on this. Good luck to you and I’m excited to hear your response. Oak Park, Michigan 08/23/2017
Hello, what is NAC? My Grandmother is 88yrs and I want to try this home remedy. Thanks.
EC : NAC is the Acronym for the supplement N-Acetyl Cysteine. Trinidad And Tobago 10/30/2017
Can you advise in a little more detail on how to take the supplement for pulmonary fibrosis and if I can implement this treatment myself or need a doctor to do So? Chandigarh 11/18/2017
My grandmother has ILD Intestinal lung disease and pulmonary hypertension she is 65 years of age and has been taking medication for the above for last 3 years .M y question is if serapeptase would help? 12/23/2017
Dear Siva,
My mother’s IPF condition is very similar to the one described by you. She is currently undergoing treatment in Mumbai with Wysolone/Cellcept/Pirfinex. She is currently on 14 hours home oxygen daily.
There has not been any improvement in her condition so far. Could you let me know your contact details, so we could exchange valuable information. 2 posts
Natalia,
I only went to the pulmonary doctor once, so I’ve never been on any conventional meds, and I’ve managed to avoid any more MRI’s and CT scans, since the initial ones. I do take a B/P med, and I am prescribed two inhalers, which I keep in case I feel short of breath at all, but I rarely need them.
My last visit to the doctor she said my lungs sounded clear, and that oxygen thing they put on your finger said 98%. Don’t know how accurate that is though.
I went through something about a month ago, a lot of coughing, had to get some mucolyxir to get that thick and sticky mucus out, but I’m back to “normal” now.
I read here on Earth Clinic several years ago, that asthma can be triggered somehow by acid reflux, and I do suspect that has a lot to do with some of my issues, so I try to eat several hours prior to bed.
But my go-to supplements for the fibrosis are serrapeptase, and I have added nattokinase, but in the past that has caused nose-bleeds for me, so I am careful with that, and Rejuvenzyme, which seems to have just about all of the ingredients in one of the items in the package that was out of my budget. Ideally, I’d take the serrapetase and revenzyme three times a day, but that has never happened, just because I don’t think about it. And then I do take the NAC with vitamin C also. But I prefer mucolyxir to NAC for mucus.
I’d like to know what caused the fibrosis, but I’m just not curious enough to go for a biopsy and have three holes in my lung from chest tubes. Curiosity killed the cat, so they say 🙂 Perhaps if I get to the point where I can’t breath I’ll change my tune. Lebanon, Tn 06/11/2018
My brother was diagnosed in February of 2017 with IPF. Where can I get these products and how are you doing now? Looking forward to your response. Posted by Chris (Seattle, WA) on 12/31/2008
NSIP Pulmonary Fibrosis:
Just diagnosed at mild to moderate stage, but had been taking NAC with Selenium twice a day and also herbal Clear Lungs, very helpful with breathing. I need it in the emergency dose of every 4 hours. The product does not claim to be a cure, but does claim to help breathing and it does and acts quickly as it claims. No side effects. My MD recommended Selenium via Brazil Nuts. My specialist prescribed more NAC, but also Prednisone, Azathioprine,whose side effects sound so horrific it seems I would be sicker than I am now.
The Albuterol spray was given at the testing site, to which I immediately felt ill and had a severe headache. I have severe congestion of the tonsils. Is this usual, the doc thought it was unrelated. I have to avoid wind, fans, forced hot air etc because it sets me off, also I have allergies.Particularly to dust and dairy.
I certainly intend to try your suggestions. Would love any input and advice. Blessings to all.
EC : NSIP = Non-Specific Interstitial Pneumonia NAC = N-Acetyl-Cysteine Howard (Cessnock, NSW, Australia) on 04/16/2008
I have pulmonary fibrosis and have been treated (without result) by the standard medical method and I am now trying systemic enzymes (dispensed by capsule containing various enzymes combined in a very specific amounts for each of the dozen or so enzymes). This treatment has only been going for 2 weeks and although there are some positive signs it is still too early to make a definitive assessment. For instance, my voice has almost returned to normal and I can now sing once more. Washington, DC 04/22/2008
There was a comment from a gentleman dated 04/16/08 for the IPF. He stated that he was on some enzymes (for 2 weeks) and has seen some improvement. I would like to know what they are: my father has IPF and I am trying to figure out what to use. thank you. 04/24/2008
To Tonja via Deirdre,
Although I have been on Neprinol for a matter of weeks I have seen some very positive improvement in my condition (IPF) and also some bonus changes unconnected to IPF.
In the matter of IPF I was having great difficultywalking any real distance 200/300 yards,especially on flat amd hilly ground and light activity in the garden (digging,weeding and moving the wheel barrow around with light loads) and 15 minutes or so would find me very breathless.Whereas, now I can work for at least 40minutes with the mower/chopping with the axe/digging with the mattoch etc and whilst I will then be quite puffef out my recovery time only takes about 7/10 minutes.
As for the “bonuses” -these can be seen in the slow dissappearence of a scar on my upper lip that has been there for many many years (I am 82 ) ,my right wrist which was fractured badly some decades ago and only had about 75% rotational movement is now as mobile as my other wrist, also I am noticing a vast improvement in my ability while driving my car,to turn and twist my neck and head to look left and right over either shoulder to check for traffic.Prior to this my flexibility in this area was quite restricted due to R/A,This brings me to another bonus ie; I no longer take anti-steroidal drugs for R/A and have no real pain in my feet and hands.
I hope my experience gives you some insight into what course of action you should take for your father,keeping in mind that all meds do not work for everyone in an identical way,but I do feel that ,as the old saying goes “If it wont help, it wont hurt”.It certainly is helping me.I am looking forward to my next chest x-ray to see if there has been any significant improvement in my lung condition(about 3 months time). Austin, Tx 10/05/2009
Has anyone had any relief for Pulmonary Fibrosis using Neprinol? How much did you take? Would also like more info on these other enzymes…Thank you! San Jose, California 02/13/2015
Hi everyone. My mom just got diagnosed with these lung problem. Please keep posting your comments. It is helping me to act quickly to help my mom. Thanks. 02/16/2015
Hello All,
My mum was diagnosed with end stage pulmonary Fibrosis. She is in palliative care at home. Since she came home from the hospital, she is much better. However any small exertion, she gets out of breathe and feels as if she is going to pass out. It is very difficult to see her suffer like this.
I have read many helpful comments on this site. Is there anyone willing to share their experience on the phone conversation? It will be greatly appreciated. My phone is 416-293-4232.
May you all always be well, happy and peaceful. Usha 02/17/2015 2115 posts
U: First item to address is greatly improving the quality of indoor air. Replace fiberglass filters w/ HEPA or HEPA Type(generic HEPA), and purchase a Negative Ion Air Purifier.
Zinc & Vit-A is critical in protecting & healing lungs. The mineral Silica is also critical in lung healing. My stomach nor Colon couldn’t tolerate silica tablets taken orally so I have added Diatomaceous Earth powder to my mineral footbath w/ noticeable improvements in my PF. The flavonoid Quercetin Dehydrate capsules taken orally will help w/ the inflammation. An herbal product named “PainRx” is a potent anti-inflammatory. Fish or Krill Oil softgels is both anti-inflammatory and promote healing throughout the body.
A good broad spectrum otc natural supplement for lung disorders is Solaray’s “Lung Caps”. Noida, India 04/07/2015
Please let me know your latest possible treatment of Pulmoiary fibrosis. my dad is running in to advance stages and needs oxygen on 24×7 now. Thanks in advance. Maneesh
M: I and others have posted remedies for this condition here http://www.earthclinic.com/cures/pulmonary-fibrosis-lung-disease-remedies.html on E.C.
Try any or all these suggestions and report back so we can help you. Texas 01/03/2016
I was dx with pulmonary aspergillosis. I had lived in 3 houses with black mold, but my cough didn’t become chronic until I caught a serious respiratory illness from one of my daycare kids around 2002, that I don’t think I ever fully recovered from.
Around 2007 an x-ray revealed 3 nodes in lower right lobe and it was determined to be A Niger.
It’s worse am/pm and after eating or being exposed to aerosol toxins. I tried many things over the years including HP, serrapeptase… anything anyone had to offer. Nothing worked. I couldn’t tolerate the oral HP, and never tried nebbing it.
I finally resorted to an expensive, complete dental revision removing/replacing all materials with more bio-compatible materials (tested for this) in 2011. Extensive, 8 hrs under conscious sedation. Numerous serious infections.
My docs believed that the fungus was adhering to fibrosis which would be eliminated with a specific protocol. The dental metals tend to adhere to fibrosis as well and complicate things, which would improve with my detox protocol.
I eliminated dairy and all processed foods that contained Calcium-anything (never 100%, btw) and began taking Bioavailable calcium, mag, and a few others basics. The only dairy I consume is occasional diluted organic whipping cream. I do eat lots of organic butter. I also started eating meat and eggs again after 25 years being vegetarian… and never felt better!
The fibrosis in my breast, which I’d had all my adult life dissolved in short order- definitely within a year. I had successfully eliminated uterine fibroids (fibrosis) about 35 years prior, which had resulted in hysterectomies in every woman in my family before me. I wasn’t giving up any body parts and found an alternative solution.
The arthritis that had been developing prior to surgery went away, as did the weird AI-like symptoms I had developed. I did experience some pain in my knee for a few months and in hindsight, I believe it was the cal deposits breaking up.
Prior to all these changes I had severe degeneration of C5/6 in my neck, vertebrae almost touching. On re-check sometime after, all the bone spurs were gone, smooth edges and the disks were nice and puffy. Total regeneration. My chiro was giddy!
Another very curious thing… every time my oxygen level is checked it’s always 98-100, even with atelectasis present, and they can’t explain it. They say my body has found some way of compensating. My challenged RBCs are now excellent since the surgery. The current HCP, who I was seeing several times a week for a couple of months, claimed that atelectasis would come and go- there one time, gone the next. I am nebbing saline and just finished taking 2 bottles of ADP (emulsified oregano oil)- 6, three x/day. Still coughing.
My ‘dental’ doc did say that eliminating ‘pulmonary’ fibrosis would take longer. It’s been 4 years. He passed last year and I’ve gotten a little lax without his guidance and support. I’m getting impatient.
Due to extenuating circumstances, I had to live in another house with bad mold and dust mites from Jan12-Jan15. I did the best I could and kept a window cracked year round. Of course, the cough got worse.
I should divulge that I am a long-term light/moderate smoker of organic tobacco. None of my HCPs have been concerned or consider it the cause or a contributing factor.
I’d really like to try Glutathione and possibly Oregano oil, but am afraid to experiment without guidance. If you know of a HCP who could supervise this in the Austin, Tx area, please let me know.
I don’t want to go to a traditional MD. I know what they have to offer and am not interested. I also don’t want to be wrongly dx’d with lung cancer, as Suzanne Somers was (she had fungus) and imprinted with fear mongering. There’s a reason I’m hosting this, and I want to change that, not ‘manage’ this the rest of my life.
Thanks, SS

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Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges

<h1>Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges</h1>

Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges

1 Laboratory of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, 3000-548 Coimbra, Portugal 2 Polytechnic Institute of Coimbra, ESTESC-Coimbra Health School, Pharmacy, 3046-854 Coimbra, Portugal 3 Nephrology Department, Coimbra University Hospital Center & University Clinic of Nephrology, Faculty of Medicine, University of Coimbra, 3000-075 Coimbra, Portugal
Correspondence should be addressed to Flávio Reis ; and Rui Alves ;
Received 13 April 2018; Revised 7 September 2018; Accepted 25 September 2018; Published 29 October 2018
Academic Editor: Kum Kum Khanna
Copyright © 2018 Sofia D. Viana et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience. The main clinical indication of rapamycin is as immunosuppressive therapy for the prevention of allograft rejection, namely, in renal transplantation. However, considering the central participation of mTOR in the pathogenesis of other renal disorders, the use of rapamycin and its analogs meanwhile developed (rapalogues) everolimus and temsirolimus has been viewed as a promising pharmacological strategy. This article critically reviews the use of mTOR inhibitors in renal diseases. Firstly, we briefly overview the mTOR components and signaling as well as the pharmacological armamentarium targeting the mTOR pathway currently available or in the research and development stages. Thereafter, we revisit the mTOR pathway in renal physiology to conclude with the advances, drawbacks, and challenges regarding the use of mTOR inhibitors, in a translational perspective, in four classes of renal diseases: kidney transplantation, polycystic kidney diseases, renal carcinomas, and diabetic nephropathy. 1. Introduction
The mechanistic (formerly mammalian) target of rapamykinase, was discovered almost simultaneously by three independent groups in the mid-1990s and coined as rapamycin and FK506-binding protein-12 (FKBP-12) target 1 (RAFT1), FKBP–rapamycin-associated protein (FRAP), and mTOR [ 1 – 3 ]. These names reflected the fact that mTOR was identified as the target of rapamycin (etymol.: Rapa- (Rapa Nui = Easter Island), -mycin (related to the antifungal properties)), which is a natural antibiotic macrolide firstly isolated from bacterium (Streptomyces hygroscopicus) extracts found on Easter Island soil samples [ 4 ].
mTOR is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, which is one of the key players of cellular metabolism that is coupled with nutrient availability, energy, and homeostasis [ 5 , 6 ]. It plays a prominent role as a molecular sensor of gene transcription and protein synthesis, tissue regeneration and repair, immunity, oxidative stress, and cell proliferation/cell death (e.g., autophagy and apoptosis) upon environmental and cellular cues (nutrients (e.g., glucose, amino acids, and fatty acids), growth factors (e.g., insulin-like growth factor-1, IGF-1; vascular endothelial growth factor, VEGF), hormones (e.g., insulin), and cytokines) [ 7 – 9 ]. Given the ubiquitous distribution of mTOR in distinct cell types throughout the body, mTOR pathway control several anabolic and catabolic processes in distinct organs/tissues including (but not restricted) the liver, lymphocytes, white and brown adipose tissue, skeletal muscle, brain, heart, and kidney [ 8 ]. Hence, impaired mTOR activity has been associated in widespread human diseases, including cancer, type 2 diabetes, cardiovascular pathology, and neurodegeneration as well as during aging [ 10 – 12 ].
Notably, accumulated evidence suggests mTOR signaling deregulation as a central player in the pathophysiology of distinct kidney diseases. Herein, we will critically discuss the advances, drawbacks, and future challenges of mTOR pharmacological inhibition in distinct renal conditions and in a bench-to-bedside perspective. 2. Overview of mTOR Components and Signaling Pathways
mTOR is a 289 kDa protein kinase encoded in humans by the MTOR gene (1p36.2). It interacts with several proteins to form two evolutionary conserved complexes among eukaryotes—mTORC1 and mTORC2. There are two common proteins shared by mTORC1/mTORC2 multimeric complexes: the positive regulator mLST8 (mammalian lethal with Sec13 protein8, also known as G β L) and the negative regulator Deptor (DEP domain-containing mTOR-interacting protein). Yet, there are unique proteins coupled to each complex: mTORC1 is associated with raptor (regulatory-associated protein of mTOR), fundamental for mTORC1 stability and a positive regulator of downstream effectors recruitment and with PRAS40 (proline-rich Akt substrate), a protein which blocks mTORC1 activity; mTORC2 is coupled with mSIN-1 (mammalian stress-activated protein kinase-interacting protein), PROTOR 1/2, and Rictor (rapamycin-insensitive companion of mTOR), a scaffold protein that displays chief roles for mTORC2 assembly, stability, and substrate recognition (e.g., Akt and SGK1) [ 7 , 11 ].
The mTOR-containing complexes also differ in terms of upstream modulators, substrate specificity, functional outputs, and sensitivity to rapamycin [ 13 ]. mTORC1 broadly senses nutrients, growth factors, mitogens, and stress signals, thus being generally associated with cell growth by regulating important cellular processes, including the translation of mRNAs into the synthesis of key proteins for proliferation, lipid synthesis, mitochondrial biogenesis, and autophagy [ 14 , 15 ]. Examples of mTORC1 downstream effectors are the lipin 1/SREBP (sterol regulatory element-binding proteins), the p70S6 kinases (S6K1 and S6K2), and the EIF4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1) [ 16 , 17 ]. In contrast to mTORC1, the control of mTORC2 by upstream modulators and downstream effector proteins is not as well understood, even though insulin and related pathways have been suggested as the main activators [ 11 ]. Nevertheless, plasma membrane localization as well as ribosome-binding through insulin-stimulated phosphatidylinositol 3-kinase (PI3K) signaling seem to have a chief role in mTORC2 regulation [ 18 , 19 ]. Phosphorylation of protein kinase B (Akt) and other AGC-family kinases (e.g., serum- and glucocorticoid-induced protein kinase 1, SGK1; protein kinases C, PKC) has been linked with mTORC2 activation, with important consequences on cell survival, cytoskeleton organization, and cycle progression [ 14 , 20 , 21 ]. Interestingly, Akt appears to have a complex dual role on mTOR, being both an (i) upstream regulator of mTORC1 (indirect activation through phosphorylation and inactivation of TSC1/TSC2 complex, who constitutively suppress mTORC1 activity through Rheb GTPase inhibition) and a (ii) downstream target of mTORC2 [ 10 , 22 ]. The activity of the two complexes is finely and mutually tuned through some feedback circuits promoted not only by upstream regulators of mTORC1 (e.g., Akt) but also by other downstream effectors of mTORC1, such as the p70S6K1 [ 23 – 25 ]. For instance, p70S6K1 phosphorylates mSIN-1 at both Thr86 and Thr389 residues and dissociates mSIN-1 from mTORC2, thus providing a negative feedback mechanism downstream of mTORC1. The loss of such reciprocal mechanistic feedback loops is observed in some mutational loss-of-function in mTOR key components, as in the case of the R81T Sin1 mutation identified in ovarian cancer patients, highlighting their clinical relevance [ 25 ]. Hence, impairments of constitutive feedback mechanisms and unexpected mTOR hyperactivation are particularly relevant when mTOR signaling modulation is envisaged. In this regard, the fact that PI3K/Akt/mTOR pathway critically regulates a plethora of physiological processes that become deregulated in a wide spectrum of pathologic conditions prompt the design of several pharmacological agents that target distinct components of this signaling cascade, as outlined in Section 3 [ 22 , 26 – 28 ].
Finally, the sensitivity to rapamycin is another important feature that distinguishes mTORC1 and mTORC2 complexes. Rapamycin does not directly inhibit the catalytic (kinase) activity of mTOR; instead, it binds to the immunophilin FKBP12 (FK506-binding protein of 12 kDa), which is a protein that couples with mTOR FKBP-rapamycin-binding domain (FRB). Even though the FRB domain is present in both mTORC1/2 complexes, it is only exposed in mTORC1, as Rictor blocks the access of FKBP12-rapamycin complex to FRB domain in mTORC2 [ 25 , 29 ]. Hence, mTORC2 is relatively resistant to the effects of rapamycin both in vitro and in vivo , although this phenomenon can be disrupted by chronic treatments [ 13 , 30 , 31 ]. 3. Pharmacological Advances and Challenges within mTOR Inhibition
The recent breathtaking advances in up- and downstream targets of mTOR, reciprocal feedback mechanistic loops, and mutational loss-of-function in mTOR key components (e.g., TSC1/2, PIK3CA, and Akt), the most common cause of mTOR signaling hyperactivity, provided new rationales for translating the mTOR basic science to the clinic. In fact, pharmaceutical companies have discovered impressive arrays of small molecules targeting PI3K/Akt/mTOR cascade elements which are currently undergoing evaluation in preclinical and clinical studies mainly in cancer and transplantation, even though mTOR inhibitors are being also considered for other pathological conditions such as rheumatoid arthritis, atherosclerosis and a wide spectrum of neurologic disorders where aberrant mTOR pathway activity is consistently observed [ 22 , 27 , 28 , 32 ]. Herein, it will be focused on the different classes of mTOR inhibitors currently undergoing preclinical/clinical studies aimed at providing new pharmacological agents with increased efficacy and a lower side effect profile. 3.1. Allosteric mTOR Inhibitors: Rapamycin/Rapalogues
Rapamycin (or sirolimus), a macrocyclic lactone, was initially described as an antibiotic agent. Nevertheless, this molecule also exhibits immunosuppressant, cytostatic, antiangiogenic, and antiproliferative properties, expanding the clinical applications to transplantation and oncology fields [ 10 ]. Rapamycin acts as an allosteric inhibitor of mTORC1, which, together with FKBP12, interacts with the FRB domain of mTORC1 blocking some of the functions of this complex (see Figure 1 ). The data suggest that rapamycin impairs mTORC1 activity mainly by preventing the association and phosphorylation of substrates into the kinase complex [ 33 , 34 ]. However, not all mTORC1 downstream targets are equally inhibited by rapamycin, with potency varying for weak versus strong substrates [ 25 ]. Moreover, and even though rapamycin does not interact with mTORC2, some studies have shown that this molecule is able to indirectly modify mTORC2 complex in a dose-, time-, and cell-type dependent manner, probably by preventing mTOR molecules from the interaction with mTORC2-specific partner protein Rictor [ 3 , 31 , 35 ]. Figure 1: Mechanisms of action of three distinct generations of mTOR inhibitors and dual PI3K/mTOR inhibitors. The first generation of mTOR inhibitors (sirolimus chemical structure selected as an example) interacts with FRB domain of mTORC1 and partially inhibits mTOR downstream signaling events. Dual PI3K/mTOR inhibitors indiscriminately bind to the ATP-binding site of mTOR and PI3K catalytic domains, thus blocking the activity of both kinases (NVP-BEZ235 chemical structure selected as an example). The second generation of mTOR inhibitors act as ATP analogs and compete with ATP only in mTORC1/2 catalytic domains without substantial effect on PI3K (AZD8055 chemical structure selected as an example). Finally, the third generation of mTOR inhibitors combines a mTOR kinase inhibitor with rapamycin within the same molecule, which allows compounds to interact with the FRB domain and also to reach mTORC1 kinase domain, acting as an ATP-competitive inhibitor (Rapalink-1 chemical structure selected as an example). Dashed arrow represents the ability of Rapalink-1 to inhibit mTORC2 kinase activity, even though the precise molecular mechanism remains to be fully addressed (mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; FRB, FKBP-rapamycin-binding domain). Elements of the scheme were drawn using the website https://smart.servier.com/ .
The fact that rapamycin has limited bioavailability led to the development of semisynthetic analogs, named rapalogues, with superior aqueous solubility and improved pharmacokinetic properties. Examples of this first-generation of mTOR inhibitors are temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus/deforolimus (MK-8669/AP23573) who share a central macrolide chemical structure yet differ in the functional groups added at C40 that significantly alter bioavailability, half-life, and administration routes (oral versus intravenous) [ 22 ]. In contrast with everolimus and ridaforolimus, temsirolimus is a prodrug that requires removal of the dihydroxymethyl propionic acid ester group after administration, becoming sirolimus in its active form [ 36 ]. Rapalogues exhibit a safe toxicity profile, with side effects such as skin rashes and mucositis being dose-dependent. Other symptoms described are fatigue, anemia, neutropenia, and metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, and hyperglycemia [ 22 ]. In this regard, it should be highlighted that rapamycin prevented insulin-mediated suppression of hepatic gluconeogenesis and impaired in vitro basal and insulin-stimulated glucose uptake in adipocytes from human donors [ 37 , 38 ]. Temsirolimus and sirolimus are also associated with pulmonary toxicity, being interstitial lung disease, risk of secondary lymphoma, and reactivation of latent infections rare side effects [ 39 ].
Since mTORC1 and mTORC2 control events intimately related to cell growth and survival, rapalogues have been extensively studied in the oncology field, with several works conducted to analyze the effectiveness of these class of molecules alone and/or in combination with standard chemotherapy in the treatment of several types of cancers [ 26 ]. Although clinically promising, the results of such studies are quite disappointing, and some putative explanations have been hypothesized. Rapalogues have some serious drawbacks in terms of the desired molecular effects, and the efficacy may be partially limited by their drug action (cytostatic rather than cytotoxic). Moreover, as rapamycin and rapalogues act only on mTORC1, treatment with any of the molecules can elicit long-term feedback loops deregulation in mTOR network, therefore leading to aberrant activity of compensatory prosurvival pathways, including the PI3K/Akt signaling network itself. This phenomenon can seriously compromise the anticancer efficacy as well as the acquisition of chemoresistant phenotypes [ 22 , 23 , 25 ]. Since mTOR is a member of PIKK-related family sharing a high degree of similarity/sequence homology within the catalytic domain with PI3K, the next logical approach was the development of ATP-competitive dual PI3K/mTOR inhibitors. 3.2. Dual PI3K/mTOR Inhibitors
As highlighted above, rapamycin and rapalogues are incomplete inhibitors of mTORC1 and elicit feedback activation of PI3K/Akt mitogenic pathways. This argues for a theoretical therapeutic advantage of dual PI3K/mTOR inhibition in terms of better efficacy and less likelihood to induce drug resistance. These new agents are a class of catalytic ATP competitive inhibitors that exert their effects by binding indiscriminately to the ATP-binding site on both mTORC1/2 and PI3K catalytic domains (see Figure 1 ), which are two crucial signaling hubs [ 26 , 40 ]. The prototype molecule in this class is the pyridofuropyrimidine PI-103, even though it was never translated into the clinic mainly because of its rapid in vivo metabolism [ 41 , 42 ]. Over the next few years, other dual PI3K/mTOR inhibitors were discovered and advanced into the clinical evaluation (phase 1 and 2 trials), namely, the imidazoquinoline derivative NVP-BEZ235 (dactolisib), GDC-0980 (apitolisib), and PKI-587 (gedatolisib) [ 26 , 40 ]. Although the appealing prospects of simultaneously targeting PI3K/mTOR, clinical studies have revealed a limited efficacy and important toxicity concerns (e.g., nausea, diarrhea, vomiting, decreased appetite, hyperglycemia, mucositis, cutaneous rash, elevated liver enzyme levels, renal failure, and hypertension). Moreover, it was proposed that dual PI3K/mTOR inhibitors suppressed a yet unidentified negative feedback loop mediated by mTORC2, which could partially explain the in vitro resistance and limited efficacy in vivo [ 25 , 43 ]. 3.3. ATP Competitive Inhibitors: mTOR Kinase Inhibitors (TOR-KIs)
More recently, a second-generation of pharmacological mTOR inhibitors have been developed. In contrast to the rapamycin analogs, these molecules exert their effects by directly blocking the ATP catalytic site that is integral to both mTOR complexes (see Figure 1 ), resulting in widespread inhibition of the mTOR signal [ 36 , 44 , 45 ]. These agents exhibit a much lower half-maximal inhibitory concentration (IC 50 ) against mTOR activity than PI3K [ 26 ]. Hence, they are more discerning in their function: the main target is the mTORC1/2 catalytic domain without substantial effect on PI3K, with an expected reduction of toxicological events associated with dual PI3K/mTOR inhibitors [ 43 ]. Remarkably, mTOR kinase inhibitors (TOR-KIs) were effective antiproliferators in cell models displaying insensitivity to the first-generation of mTOR inhibitors [ 46 , 47 ]. The first such compound was PP242, with numerous other TOR-KIs subsequently discovered, including Torin 1 and its sister Torin 2, AZD8055, TAK-228, and CC-223, some of them currently undergoing phase 1/2 clinical evaluation in neoplastic disorders [ 25 , 26 ]. Nevertheless, mechanisms of resistance were already reported for these second generation of compounds, highlighting the many adaptive skills of PI3K/Akt/mTOR network upon modulation of any key component [ 25 ]. Among several reasons that may concurrently explain such discouraging results are feedback loops dysregulation as well as a wide range of mTOR mutations responsible for the increased catalytic activity of both mTORC1/2 complexes, rather than a direct active-site mutation interfering with drug binding [ 48 – 50 ]. 3.4. New Generation: RapaLink-1
Considering the poor efficacy, resistance mechanisms, and severe side effects described for the class of drugs previously mentioned, an attempt to develop a third generation of mTOR inhibitors have been recently outlined. Through exploitation of both ATP- and FRB-binding sites of mTOR, the new molecule RapaLink-1 combine the high affinity of rapamycin for mTORC1 with the effective kinase inhibition of the TOR-KI MLN0128, which is a highly selective structural analog of PP242 that is currently in clinical trials [ 50 ]. The linker portion between these two molecules—a polyethylene glycol unit—does not disrupt rapamycin binding to FKBP12 or the FRB domain of mTOR, thus leveraging the high selectivity and affinity of rapamycin for mTORC1 and the “deliver” of MLN0128 to the ATP site of mTORC1 [ 50 , 51 ]. Notably, RapaLink-1 was effective in the inhibition of both mTORC1 and mTORC2 downstream targets (mTORC1 (S6K, 4EBP1) and mTORC2 (Akt)) at doses between 1 and 3 nM, suggesting that it is also able to suppress the catalytic activity of both mTORC2 components through direct or indirect mechanisms that remain to be elucidated (see Figure 1 ). This drug was found effective in reversing resistance of breast cancer due to mTOR FRB or kinase domain mutations [ 50 ]. Despite its size, Rapalink-1 can cross blood-brain barrier and has shown increased efficacy in a glioblastoma cell model as well as in a genetically engineered in vivo model of brain cancer, when compared with earlier mTOR inhibitors [ 52 ]. Moreover, this compound did not display significant toxicity events when given intraperitoneally in mice and was also recently suggested as a possible new alternative to treat and prevent the development of alcohol use disorder (AUD) [ 53 ]. Overall, Rapalink-1 shows an appealing potency profile compared with earlier mTOR inhibitors which encourage next clinical evaluation. Nevertheless, further preclinical studies aimed at establishing whether Rapalink-1 has immunosuppressive properties is an inductor of autophagy and/or disrupts homeostatic mTOR feedback loops deserve to be better exploited. 4. The Role of mTOR in the Kidney
As previously mentioned, mTOR plays a major role in the regulation of cell proliferation and growth, mainly acting as a metabolic sensor, while low cellular energy supply suppresses mTOR activation and high metabolic input fuels mTOR activation. Whereas, the precise roles played by mTORC1 and mTORC2 complexes in the different types of renal cells is not fully unveiled during development nor in the adulthood, it is suggested that mTOR signaling pathways impact glomerular and tubulointerstitial renal physiological processes [ 54 ].
The same also holds truth under conditions of kidney injury. Podocytes, the most vulnerable elements of all kidneys, can adapt to stressful conditions (e.g., metabolic, immunological, and toxic) acquiring a hypertrophic phenotype [ 55 , 56 ]. Noteworthy, this compensatory mechanism related to size control seems to be mTOR-mediated [ 57 , 58 ]. In fact, features like podocyte damage and proteinuria are observed in both animal models and transplanted patients upon rapamycin treatment, strengthening the concept that mTOR activity is paramount for adaptive compensatory mechanisms in response to glomerular insult [ 59 – 63 ]. Moreover, studies using genetic models revealed that besides mTORC1 complex, mTORC2 and its downstream target Akt2 also play a role in renal glomerular functions, including podocyte stress surveillance and survival of remaining podocytes in conditions of nephron mass reduction [ 58 , 64 ]. Furthermore, prevention of mTORC2-Akt2 activation by rapamycin in biopsy tissue from kidney transplant patients was accompanied by increased glomerular apoptosis [ 64 ], reinforcing the notion that mTORC2 (along with mTORC1) might contribute to rapamycin-induced proteinuria.
Regarding kidney tubules, much less is known concerning the physiological (and pathological) role of mTORC1 and mTORC2. Apart from proteinuria, subjects under sirolimus therapy may develop hypophosphatemia and hypokalemia; since phosphaturia is a reliable outcome, and considering that in vivo mTORC1 inhibition does not seem to affect the apical phosphate reabsorption machinery [ 65 ], it could be conjectured whether mTORC1 could affect the basolateral efflux pathways in proximal tubular cells or other unknown hormonal components of phosphate homeostasis. Further research, namely, using mTORC1 ablation in the proximal tubule, is advisory to clarify the precise mechanisms. Concurrently, in vitro data have been suggested on the involvement of mTORC2 in renal tubular Na + balance regulation [ 66 ]. This hypothesizes, if further confirmed in vivo , might be important for some clinically relevant conditions, such as salt-sensitive hypertension or volume overload occurring with congestive heart failure. 5. mTOR Inhibition and Renal Diseases 5.1. Kidney Transplantation
The true challenge of transplantation research, in addition to the specific advances in surgery, was to improve knowledge about the complexity of the immune system and to design and synthesize drugs able to counteract acute rejection. In the early 1950s, even without effective solutions to prevent rejection, the first successful kidney transplant between genetically related donors was performed, thereby minimizing the role of HLA system, which would ultimately be discovered in 1958. In fact, in 1954, the kidney transplant performed by the Boston group between identical twins was crowned by huge success, with the kidney receptor surviving eight years posttransplant. However, it was imperative to extend the transplantation to unrelated living donors and deceased donors; however, in those cases, the incidence of rejection, with consequent organ loss, remained very high. With the discovery of the first calcineurin inhibitor and its use in clinical practice in 1983, a new era dawned for graft and patient survival. Later, in 1994, a more potent calcineurin inhibitor came into use: tacrolimus. Tacrolimus, in combination with mycophenolate mofetil or mycophenolate sodium (MMF/MPA), showed a remarkable impact on the incidence of acute rejection, which declined to around 5% and 15%, respectively, with a significant improvement in graft and patient survival to over 90% in the first year after transplantation [ 67 ].
This advance notwithstanding intensive experience with calcineurin inhibitors has progressively shown their “dark side”, with side effects frequently related to high drug blood concentrations. Adverse effects such as acute and chronic nephrotoxicity, worsening risk of cardiovascular disease, new onset diabetes after transplantation, increased incidence of neoplasms, and viral infections such as CMV, BKV, and oncogenic viruses have been and still are the Achilles’ heel of these drugs, and even today continue to fill discussion forums. At the heart of the controversy remains the permanent search for the balance between receiving adequate immunosuppression to prevent graft rejection and minimizing adverse effects, especially nephrotoxicity and cardiovascular events, which continue to be the main cause of death.
Despite all the undisputable therapeutic progress, improvement in long-term graft survival remains lacking. Several factors have been identified to this end, namely, graft quality (older donors, and/or with expanded criteria) and alloantibody-mediated chronic rejection [ 68 ]. This multifactorial problem stimulated research on new drugs, alternatives to calcineurin inhibitors, and/or novel immunosuppression strategies which could simultaneously provide two key transplantation objectives: a better long-term graft survival and fewer toxic and adverse effects on the graft and receptor.
The use of mTOR inhibitors in kidney transplantation started in 1990 with the discovery of rapamycin (sirolimus). Exciting results were observed when sirolimus was combined with cyclosporine and prednisone, leading to a significant reduction in the incidence of acute rejection when compared to azathioprine or placebo, despite persistent high triglyceride levels [ 69 , 70 ]. It was readily observed that the use of these new immunosuppressant drugs could be an attractive alternative to the calcineurin inhibitors, and thus two immunosuppressive strategies were proposed: either the use of mTOR inhibitors without calcineurin inhibitors or maintenance of calcineurin inhibitors in the early posttransplant period with a switch to mTOR inhibitors shortly thereafter (early conversion). The exclusion of calcineurin inhibitors was tested in some studies [ 71 ], but with disappointing results due to the high number of acute rejection episodes. Only one center achieved satisfactory results when comparing sirolimus and IL2R antibody induction, calcineurin inhibitor-based regimen [ 72 ]. Induction with lymphocyte-depleting antibodies in two therapeutic strategies comparing sirolimus with cyclosporine also showed no advantage, and there was no difference in graft and receptor survival in the first year. This showed that immunosuppression without calcineurin inhibitors was not a good alternative and suggested that sirolimus alone was less potent in controlling the immune response in the early posttransplant period. This disadvantage was not resolved by increasing the dose, a strategy which was associated with more adverse effects [ 73 ].
Considering early conversion to mTOR inhibitors, a study on conversion from cyclosporine A (CsA) to sirolimus at three months posttransplantation, combined with MMF and oral steroids, showed that eGFR in the first year was significantly higher in the sirolimus group (68.9 vs. 64.4 mL/min), with no statistically significant difference regarding receptor and graft survival [ 74 ]. The incidence of acute rejection occurred mainly after the suspension of corticosteroids, but the difference was not statistically significant. It should be noted that the sirolimus group had higher serum triglycerides as well as more cases of diarrhoea, aphthous ulcers, and acne. Another randomized study with early conversion of cyclosporine to a different mTOR inhibitor—everolimus—while maintaining mycophenolate mofetil (MMF) observed that the everolimus group showed a significant improvement in eGFR (71.8 vs. 61.9 mL/min). These patients, however, also had a higher incidence of biopsy-proven acute rejection (10 vs. 3%) [ 75 ]. The follow-up of these patients at five years confirmed that in the first year posttransplant grafts presented better function, but also a higher incidence of acute rejection [ 76 ]. Another study following the same line of research found a better eGFR in the sirolimus group compared to the calcineurin inhibitor at one-year posttransplantation, but after two years this difference disappeared [ 77 ]. Biopsy-proven acute rejection biopsy was similar in both groups, but the number of deaths was higher in the calcineurin inhibitor group. In both studies, however, a higher incidence of adverse effects was observed, leading to the discontinuation of the mTOR inhibitor.
In the ZEUS study, designed to analyze the incidence of anti-HLA antibodies (specific to the donor), we found significantly higher levels in patients undergoing mTOR inhibitors. It is unknown whether this effect was drug-related or due to corticosteroid suspension [ 78 ].
Faced with somewhat disappointing results from the isolated use of mTOR inhibitors and admitting the undisputed superiority of calcineurin inhibitors (CNI) in the control of rejection, researchers sought to explore the complementarity of both drugs, while minimizing their drawbacks and enhancing their advantages. It should be noted that the combination of mTOR inhibitors and CsA had previously been tested in the 1990s, with a low incidence of acute rejection at the expense of a large number of adverse reactions, mainly related to the high doses that were practiced at the time [ 79 ]. Sirolimus doses should vary according to the type of calcineurin inhibitor. In fact, the combined administration of sirolimus with cyclosporine increases its toxicity, implying that a lower dose should be used than with tacrolimus [ 80 ]. For these reasons, clinical trials started testing the combination of mTOR inhibitors and calcineurin inhibitors using lower doses. In the work by Langer et al., the combination of everolimus (whole blood concentration target blood level > 3 ng/mL) with very low dose tacrolimus (target blood level 2–4 ng/mL) resulted in a low incidence of acute rejection episodes, without compromising graft function [ 81 ]. The combination of sirolimus with a reduced exposure to tacrolimus also showed a low incidence of acute rejection and a trend towards better graft function [ 82 ]. A meta-analysis focusing on this topic concluded that the association of mTOR inhibitors with low-dose tacrolimus effectively preserves graft function without a significant impact on patient survival and graft rejection when compared to the standard dose of tacrolimus [ 83 ]. The most frequently found adverse events in patients were dyslipidaemia and new-onset diabetes after transplantation (about 60 and 38%, respectively), followed by surgical wound complications and hypertension. In accordance with current experience, the combination of mTOR inhibitors with tacrolimus in low dose appears to be a very potent immunosuppressive regimen, considering that the former adverse effects are dose-dependent.
The challenge of combining efficacy and safety while preventing episodes of acute rejection, and maintaining good long-term graft function, is well present in the ongoing TRANSFORM trial (Advancing renal TRANSplant efficacy Outcomes with an eveRoliMus-based regimen) ( NCT01950819 ), whose final conclusions are expected in 2018 [ 84 ]. In this trial, the mTOR inhibitor everolimus combined with a low-dose calcineurin inhibitor is compared to mycophenolate with standard CNI exposure, and the long-term effects are observed. The significant number of patients enrolled and three-year follow-up period makes this the largest randomized study ever undertaken in kidney transplantation and is expected to clarify the advantages or disadvantages of utilizing the combined strategy. In the preliminary results published at 12 months, eGFR was similar in both arms [ 85 ], and the study also met its key secondary endpoint showing noninferiority with respect to the composite endpoint of tBPAR, graft loss, and death [ 85 ]. A decrease in the incidence of viral infection by cytomegalovirus (3.5 vs. 12.5%) and BK virus (3.9 vs. 7.2%) was observed [ 85 ]. The preliminary analysis was able to demonstrate the noninferiority of this therapeutic regimen, with the advantage of a lower incidence of viral infections.
According to current knowledge, it is possible to conclude that mTOR inhibitors in kidney transplantation may be satisfactory and effective when applied in the following two strategies: in combination with low-dose calcineurin inhibitors or in early conversion that provided patients with moderate-to-high immunological risk are excluded. 5.2. Polycystic Kidney Disease
Polycystic kidney disease (PKD) is a clinically and genetically heterogeneous group of monogenic disorders. This pathologic entity comprises several Mendelian diseases including autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and atypical PKD forms [ 86 , 87 ]. ADPKD is the most common life-threatening hereditary renal disease, with an incidence of 1 : 400 to 1 : 1000 individuals [ 88 ]. Disease severity is highly variable, displaying distinct phenotypes ranging from manifestations in utero or during infancy (very early onset (VEO) disease) to clinically silent disease well into the second or third decade of life [ 89 , 90 ]. In contrast, ARPKD typically presents much earlier (1 : 20000 live births among Caucasians). With advancing clinical course, ARPKD pathophysiological features often resemble the pattern of ADPKD, even though a more severe phenotype is often observed [ 87 ].
ADPKD is a chronic entity characterized by the appearance of cysts in both kidneys, which may also occur in other organs such as the liver, ovary, pancreas, spleen, and the central nervous system [ 91 ]. It is the most frequent hereditary kidney disease that progresses to end-stage kidney disease by the 5th or 6th decade of life, reaching a prevalence of around 8–10% in patients on dialysis [ 91 ]. Kidney size can reach significant dimensions as a consequence of the progressive increase in the volume of cysts in about 5% to 8% of the nephrons, leading to a gradual decline of renal function [ 91 ]. Renal capsule distension and compression of surrounding renal tissue may lead to complications such as hypertension and chronic pain, whereas the accumulation of urine can precipitate parenchymal infection. The CRISP study (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease) showed that renal volume and cysts increase at an exponential rate of about 5% per year and that this increase, as detected by magnetic resonance imaging, is accompanied by progressive deterioration in renal function [ 92 ].
About 85% of ADPKD is caused by mutations in the PKD1 gene which encodes polycystin-1, a large glycosylated integral membrane protein receptor present in the plasma membrane and in the renal tubular epithelium as well as in the bile and pancreatic ducts [ 93 ]. The remaining 15% are the result of mutations in the PKD2 gene encoding polycystin-2 [ 94 ]. Polycystin-1 is an adhesion molecule thought to be involved in cell-cell and cell-matrix interactions, whereas polycystin-2 is similar to a voltage-gated calcium channel. Both interact to regulate calcium influx [ 95 ]. Mechanisms of cystogenesis are not fully understood, but disruption of ciliary structure and changes in the cyclic AMP (cAMP) secondary to changes in intracellular calcium are responsible for cell proliferation, fluid secretion, and extracellular matrix composition [ 91 ]. These pathophysiological changes are mainly due to the overactivation of EGFR, cAMP, and mTOR pathway, leading to great interest in research regarding the inhibition of this signaling pathway in the treatment of this disease [ 96 , 97 ]. Given that ADPKD patients carry deletions in adjacent genes such as PKD1 and tuberous sclerosis complex 2 (TSC2) which are responsible for the polycystin 1 and tuberin proteins, the hypothesis of a common cystogenic pathway has been advanced [ 98 ]. In fact, the TSC2 gene is responsible for the modulation or inactivation of the cell growth signals and proliferation promoted by serine-threonine kinase mTOR, which is abnormally activated in the cystic epithelium of patients with ADPKD. Polycystin 1 inhibits mTOR signaling through its interaction with tuberin. In the absence of this regulatory function, hyperactivity of the mTOR pathway results in a translational increase of the protein through the phosphorylation of S6K and 4EBP1, leading to proliferation, cell growth, and progression of cystogenesis [ 98 , 99 ].
Initial studies conducted in preclinical models aimed at establishing whether mTOR inhibition through rapamycin or everolimus (first generation of mTORC1 inhibitors) could ameliorate PKD (see Figure 2 ). The majority of these studies have reported that these agents elicited a long-lasting reduction in kidney size and an improvement of renal function in rodent models of ADPKD, late-stage nephronophthisis, and models that are not orthologous to any known human mutation [ 98 , 100 – 104 ]. Nevertheless, a lack of efficacy was observed in the PCK rat model of ARPKD, Han:SPRD female rats, and early-stage nephronophthisis pcy mice [ 97 , 101 , 105 ]. Rodent models limitations along with a more prominent role of mTOR activity in later phases of the disease were possible explanations suggested by former authors. In light of these studies, mTOR activity inhibition has shown promising results as a therapy to retard the PDK course [ 104 ]. Advances in animal models have been recently established in the PKD field. One example is the Vil-Cre;Pkd2 f3/f3 mice, a ADPKD standardized model showing an important temporal cystic phenotype similar to what occurs in human ADPKD. Interestingly, this new preclinical tool has provided new insights into translational medicine, corroborating the involvement of mTOR pathway (mTORC1–CDK1/cyclin axis) in ADPKD pathophysiology and the efficacy of rapamycin treatment protocols in the improvement of mice survival, cystic phenotype, and renal function [ 106 ]. Finally, it is important to emphasize that both mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin-insensitive) complexes are hyperactivated in PKD [ 97 , 98 , 107 ]. Hence, the use of mTOR kinase inhibitors (that target both mTORC1 and mTORC2) have been hypothesized as a promising strategy to slow cystic kidneys proliferation and improve kidney function. Interestingly, a high-throughput phenotypic screening of kinase inhibitors showed a potent inhibitory activity in cyst size inhibition for most mTOR inhibitors, and a most notable profile was found for Torins 1 and 2 [ 108 ]. Additionally, a preclinical study using the Cy/+ rat model of ADPKD highlighted that PP242, another mTOR kinase inhibitor, is able to slow cyst growth and improve kidney function [ 109 ]. The influence of mTOR tissue concentration on cyst volume was also evaluated by Novalic et al. which conducted an animal model study using low (3 ng/mL) vs. high (30–60 ng/mL) sirolimus concentrations at different stages of the disease. Only the high-dose group, at the early stage, showed histologically proven inhibition of cystogenesis and regression of cysts, pointing out that effective mTOR inhibition leads to a delay in cyst development and renal volume stabilization, but require higher doses and longer exposure to the drug [ 110 ]. Overall, an abundance of preclinical evidence suggests that mTOR inhibitors effectively slow cyst growth, even though the specific role of mTOR complexes is still poorly understood [ 104 ]. Figure 2: Pharmacological inhibition of mTOR network in renal diseases. A plethora of evidence highlights mTORC1 and/or mTORC2 hyperactivation through deregulation of feedback mechanisms that constitutively regulate mTOR network as well as acquired mutations on mTOR key components, as exemplified in the figure. Herein, it is summarized distinct classes of mTOR inhibitors that are currently available in clinical practice and/or in R&D trial stages in four classes of renal diseases: kidney transplantation, polycystic kidney disease, renal carcinoma, and diabetic nephropathy. The main outcomes from mTOR inhibition are highlighted with green color. Elements of the scheme were drawn using the website https://smart.servier.com/ .
Because inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst growth expansion and preserves kidney function in PKD preclinical models, the next logical step was to test the effects of mTOR inhibitors (currently in clinical use as immunosuppressants) on cyst growth in human clinical trials. However, results from large randomized clinical trials testing both sirolimus and everolimus in ADPKD patients are still controversial. In the human randomized study conducted by Serra et al., and after 18 months of observation, patients with eGFR > 70 mL/min and kidney volume of about 1000 mL, rapamycin did not modify the eGFR, nor the total renal volume, compared to the control group, while albuminuria increased in the treated group [ 111 ]. In another study, higher doses of sirolimus seemed to stabilize cyst volume, comparing to the conventional therapy-treated patients [ 112 ]. The evaluation of the effects of another mTOR inhibitor-everolimus on ADPKD was also performed in a 2-year study that included placebo controls, but the treated group consisted of patients at an advanced disease (stage II or III), and an average kidney volume greater than 1500 mL. It was observed that in treated patients, cysts volume growth rate and renal parenchyma decreased; however, at the end of the study, no eGFR significant difference was found [ 113 ]. Stallone et al. also conducted a prospective and randomized study to evaluate the effects of rapamycin on type 1 ADPKD. Patients with eGFR between 40 and 80 mL/min/1.73 m 2 were divided into three groups receiving ramipril. In two of those groups, a low dose of rapamycin (through levels of 2–4 ng/mL) and a high dose (through levels of 6–8 ng/mL) were given. At 24 months, the authors did not observe any significant difference between treated patients, either in total kidney volume, cystic volume, or estimated creatinine clearance, and it was found that patients receiving rapamycin showed increased urinary protein excretion [ 114 ].
Overall, these clinical results were largely disappointing, taking into account the promising effects of mTOR inhibition in PKD animal models and retrospective studies of kidney transplant recipients undergoing immunosuppression with mTOR inhibitors who displayed reduced liver cystic phenotype [ 115 , 116 ]. Some hypothesis has been figured out to explain such discouraging clinical results. Divergent approaches in terms of sample acquirements, use of different mTOR inhibitors/doses and biomarkers evaluation between experimental groups, may help to explain the lack of clinical efficacy of this class of drugs. In fact, kidney volumes have been extensively used as a surrogate endpoint of disease progression. However, therapeutic strategies that halt kidney enlargement does not necessarily improve renal function, and this is particularly relevant in ADPKD patients who constitutively display enlarged kidneys, even though the renal function is maintained for many years. Hence, from the clinical viewpoint, more adequate biomarkers to assess the efficacy of mTOR inhibition in ADPKD have been proposed, namely, the measurement of changes in GFR, serum creatinine level, and the urinary protein : creatinine ratio [ 116 – 118 ]. Another important feature may rely on the fact that mTOR inhibitors used in these trials may exhibit inadequate tissue penetration at clinically tolerable doses [ 119 , 120 ]. In this regard, the mTOR kinase inhibitors appear to have a low side effect profile besides their ability to inhibit both mTORC1 and 2 complexes [ 109 , 121 ]. Taken together, and until now, the results of mTOR inhibition therapy in ADPKD in humans, contrary to the impression left by animal model studies, does not consistently confirm the beneficial impact on renal volume or function. On the other hand, the high dose required to show some efficacy increases the adverse effects incidence, namely, the increase in urinary protein excretion. 5.3. Renal Carcinomas
Renal cell carcinoma (RCC) accounts for 2 to 3% of all adult malignancies and is the most common type of kidney cancer [ 89 ]. It develops from the proximal tubular cells and is histologically classified as clear cell RCC (ccRCC, ~85%) and nonclear cell RCC (nccRCC, ~15%). ccRCC is frequently associated with the von Hippel-Lindau (VHL) tumor suppressor mutational loss of function and subsequent accumulation of hypoxia-inducible factor (HIF) proteins, leading to the aberrant activation of HIF target genes that regulate angiogenic factors (vascular endothelial growth factor A, epidermal growth factor receptor type 1, platelet-derived growth factor B chain, and transforming growth factor), glycolysis, and apoptosis [ 122 ]. Yet, other driver mutations are also involved in the ccRCC development, including those responsible for the constitutive increase in mTOR activation [ 123 , 124 ]. For example, loss-of-function mutations of PTEN, a negative regulator of mTOR through the PI3K/Akt pathway, are found in nearly 5% of RCC patients. Moreover, loss-of-function mutations of TSC1/TSC2 genes that lead to the inactivation of TSC—a negative regulator of mTOR—are present in patients with tuberous sclerosis, a population particularly predisposed to the development of RCC [ 125 , 126 ].
RCC is a highly vascularized malignancy and has been relatively resistant to traditional chemotherapy; therefore, the focus of current treatments relies in (i) cytokine-based immunotherapy (e.g., IFN- α ), (ii) VEGF receptor-associated tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, and axitinib), (iii) anti-VEGF monoclonal antibody, and (iv) mTORC1 inhibitors, taking into account their potential to simultaneously inhibit both tumor cell proliferation and angiogenesis [ 122 , 127 ]. In fact, mTOR has presented itself as a valid target for the treatment of RCC, and both everolimus and temsirolimus (first generation of mTOR inhibitors) have EMA- and FDA-approved indications for the treatment of RCC particularly in advanced and/or metastatic RCC patients as well as in patients refractory to anti-VEGF therapy (see Figure 2 ) [ 128 , 129 ]. Retrospective studies carried out to compare efficacies of everolimus and temsirolimus in mRCC patients suggest that everolimus treatment appears more favourable than temsirolimus, even though prospective trials are needed to confirm these results [ 122 ]. The five-year survival of metastatic RCC has been improved after application of mTORC1 inhibitors, even though clinical data is somewhat mixed and the utility of these agents in advanced and/or metastatic RCC (alone or combined with VEGF inhibitors) is currently controversial based on the results from more recent clinical trials (e.g., METEOR and Checkmate 025) [ 127 , 129 – 132 ]. These observations are aligned with the poor efficacy of rapalogues in other pathological conditions as they only partially block mTOR signaling. Furthermore, incomplete inhibition of mTORC1 often induces feedback activation of procancerous signaling cascades (e.g., PI3K/Akt and ERK/MAPK).
Recent research efforts have been placed in other classes of mTOR inhibitors [ 128 , 133 ]. Cho and colleagues tested the antitumor efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, alone or in combination with sorafenib in renal cancer xenografts. The combined protocol showed positive results with enhanced apoptosis and reduction of renal cancer cell proliferation [ 134 ]. Another preclinical study focused on AZD2014, a dual mTORC1/2 inhibitor, showed higher in vitro efficiency in the inhibition of RCC cell survival and growth as well as RCC cell apoptosis when compared with conventional mTORC1 inhibitors (rapamycin), providing evidence for clinical trials using AZD2014 in RCC treatment [ 135 ]. Nevertheless, a randomized phase II study of AZD2014 versus everolimus in anti-VEGF-refractory metastatic RCC showed inferior progression-free survival (primary endpoint) and overall survival with this TOR-KI, despite favourable toxicity and pharmacokinetic profiles (secondary endpoints) [ 136 ]. More recently, a novel, selective, and orally available mTOR-KI—XL388—was found to inhibit the survival and proliferation of both established and primary human RCC cells. XL388 was significantly more potent in RCC cell death than rapalogues and showed efficacy in 786-0 RCC tumor growth in nude mice. Moreover, this molecule was also able to elicit HIF-1 α /2 α downregulation in RCC cells with putative antiangiogenic effects, strengthening the value of XL388 for future clinic evaluation [ 137 ]. Overall, future studies are needed to translate new evidence from basic research into novel multitargeted agents of mTOR network modulation within RCC. 5.4. Diabetic Nephropathy
Diabetic nephropathy (DN) is a common complication of type 1 and type 2 diabetes mellitus and is the leading cause of end-stage renal disease (ESRD) worldwide. Clinically, DN is characterized by gradually worsening of albuminuria and GFR decline, in a process that seems to start by glomerular podocyte damage and loss, then progressing to fibrosis of renal glomerulus and of tubulointerstitial region cells. All kidney cell types, including podocytes and mesangial, endothelial, and tubulointerstitial cells, are affected. In opposition to the thesis that DN progression is mainly caused by glomerular protein leakage, it is currently accepted that the glomerular filtration barrier and the tubulointerstitial compartment are an entire dynamic unit that participates in disease evolution.
mTOR pathway signaling abnormalities seem to be present in all the key steps of DN progression, including (i) podocyte damage and loss, an early event in DN that further causes glomerulosclerosis; (ii) overactivation of mesangial cells that promotes increased ECM synthesis and decreased degradation of damaged podocytes; (iii) glomerular endothelial cells and mesangial cell crosstalk that precedes glomerulosclerosis; and (iv) fibrosis and epithelial-to-mesenchymal transition in tubulointerstitial cells [ 11 ]. Although the precise mechanisms remain to be clarified, accumulating experimental and clinical evidence supports a major role of mTOR pathway disturbances in DN progression.
Collectively, diabetes is closely linked with conditions that cause mTOR activation, namely, excessive caloric intake, even when preceding obesity, insulin resistance, and overt hyperglycemia development. Activation of mTOR complexes 1 and 2 promotes fat deposition in the adipose tissue [ 138 , 139 ], which is in agreement with the rapamycin-induced hyperlipidemia seen clinical practice [ 140 ]. In conditions of overt diabetes, hyperglycemia further exacerbates mTORC1 activation due to inhibition of AMPK phosphorylation [ 141 ]. Concerning the kidney tissue, mTOR activation by diabetic conditions is related to both glomerular and tubulointerstitial changes of DN. Podocyte hypertrophy is a pivotal and early step in the glomerular hypertrophy that precedes proteinuria development and irreversible structural changes, culminating in glomerulosclerosis and nephron loss in DN [ 142 ]. Importantly, accumulating evidence from animal models of DN has suggested that mTORC1, via S6K1, participates in such process of renal hypertrophy. The role played by mTOR in podocyte function in conditions of DN was better clarified by the results of two experimental studies based on podocyte-specific genetic deletion of critical components of the mTOR signaling pathway [ 58 , 143 ]. Briefly, these studies make use of two distinct models to show that mTORC1 overactivation in nondiabetic mice caused a glomerular disease closely resembling DN, while podocyte-specific inhibition of mTORC1 activity protected mice from DN development [ 58 , 143 ]. Altogether, these studies strongly supported the idea that mTORC1 inhibition could be an effective therapeutic strategy against DN development. A drawback of this approach was the development of proteinuria when raptor expression was ablated in podocytes, which is in line with the known proteinuric effect of rapamycin treatment in both animal models and humans [ 59 – 63 ]. Other relevant metabolic side effects of rapamycin should be also noticed at this point, including hyperglycemia, insulin resistance, and dyslipidemia, which seem to be related to glucose and lipids metabolism in the pancreas and in the peripheral insulin resistant tissues (liver, adipocyte tissue, and muscle), as previously reported in animal and human studies, some of them from our own group [ 37 , 144 – 150 ].
Apart from impaired mTOR signaling in podocytes that contributes to podocyte loss, mTORC1 activation seems to be associated with renal hypertrophy and matrix expansion, overexpression of type IV collagen, fibronectin, and laminin [ 11 ]. mTOR inhibition by rapamycin prevents these effects and ameliorates the key glomerular changes found in DN, such as hypertrophy, basement membrane thickening, and mesangial matrix accumulation, accompanied by a decrease in albuminuria [ 142 , 151 ]. Regarding interstitial fibrosis, mTOR seems to be able to stimulate fibroblasts proliferation, collagen synthesis, and expression of profibrotic cytokines, such as TGF- β 1 and CTGF, which are pivotal players in the tubulointerstitial damage, a crucial feature of DN [ 142 , 151 ]. Finally, mTOR seems also to participate in the epithelial-to-mesenchymal transition, a mechanism that is inhibited by rapamycin [ 142 , 152 ].
To conclude, accumulating evidence, mostly from animal models, shows that mTOR activation might have a role on DN progression by acting on different kidney cell types and mechanisms, suggesting that mTOR inhibition could be, in theory, an attractive therapeutic strategy to overcome DN. However, the recognition of relevant side-effects in transplanted patients treated with rapamycin, such as hyperglycemia, insulin resistance, and dyslipidemia, may explain the scarceness of preclinical studies and lack of clinical trials using mTOR inhibitors to prevent or modify DN course (see Figure 2 ). 6. Conclusions and Future Directions
The mTOR pathway is an exciting area of research in many biomedical areas of knowledge, including aging, metabolism, neurobiology, oncobiology, and cardiovascular and renal diseases. Regarding the kidney, activation of mTOR complexes (mainly mTORC1) has been recognized to participate in a multiplicity of renal processes underlying the development of glomerular and tubular damage/fibrosis, such as regulation of podocyte size (hypertrophy and/or proliferation), epithelial-to-mesenchymal transition, and tubulointerstitial inflammation.
Inhibition of mTOR using rapamycin (sirolimus) or everolimus (a rapalogue), alongside with other immunosuppressive agents and depending on the immunological risk, has been a well succeeded strategy to improve outcomes in renal transplanted patients, regardless of the possibility of drug-induced proteinuria and other metabolic side-effects, which should be closely monitored and controlled. However, further clinical data is still needed to understand the putative benefits of mTOR inhibitors against the development of certain types of cancers and viral infections in transplanted patients.
Concerning PKD, in particular, the autosomal dominant form (ADPKD), the few clinical data available with mTOR inhibition was unable to confirm the preclinical studies in animal models. Therefore, clinical trials with sirolimus and everolimus have not improved renal volume or function at doses that do not cause significant adverse effects, namely, the increase in urinary protein excretion. Currently, there are not enough data to propose mTOR inhibition in PKD clinical practice. Further disclosure of (i) mechanistic insights of mTOR complexes in PKD pathophysiology, (ii) assessment of more potent and specific mTOR inhibitors, and (iii) careful systematization of clinical trials is paramount to overcome current drawbacks that postpone the translation of mTOR modulation from the benchside to PKD clinical practice.
As regards to RCC, in particular, in advanced and/or metastatic forms, the first generation of mTOR inhibitors (temsirolimus and everolimus) is already in clinical use and has been showing some efficacy, particularly when combined with VEGF modulators. However, the clinical data available remains controversial, namely, due to resistance-acquired phenomena and activation of prooncogenic pathways that limit the long-term use and outcome. Therefore, new pharmacological strategies targeting the mTOR network are currently under preclinical evaluation, which is focused on mTOR-KIs and dual PI3K/mTOR inhibitors.
Regarding the possibility of using mTOR inhibitors to prevent the progression of DN, rapamycin has been shown an ability to ameliorate mesangial expansion, glomerular basement thickening, and release of proinflammatory cytokines or chemokines by monocytes and macrophages. In spite of this amount of promising preclinical data, rapamycin is associated with some metabolic and renal side-effects, namely, insulin resistance and proteinuria, which could compromise its wide-spread use in some conditions. It should be noted that most of the actual knowledge on mTOR pathway in DN was obtained by using pharmacological inhibition of mTORC1 with rapamycin; nevertheless, it has been suggested by studies using animal models that mTORC2 activation also has a role in DN, which should be further exploited.
Although remarkable insights have been achieved over the last years, there is an ample room to improve our knowledge regarding the roles played by mTOR complexes and pathways in kidney physiology and pathogenesis of several renal diseases. In particular, further studies are required to disclose the precise mechanisms underlying the glomerular and tubulointerstitial actions of mTORC1 and mTORC2 in order to improve management of renal diseases and to reduce glomerular side effects and proteinuria reported with the traditional mTOR inhibitors currently available. Further insights are also still needed concerning the upstream regulation of mTOR, the identification of downstream mTOR targets, and, importantly, the specific role played by the regulatory proteins that interact with mTOR in both mTORC1 and mTORC2 complexes, such as Deptor, in order to unveil the impact of the mTORC1-mTORC2 interactome. Likewise, further research, particularly in the clinical setting, is required regarding the impact of mTOR inhibition in immune cells and the ability to ameliorate age-related cellular decline. Finally, the insights hopefully coming in the near future from the studies ongoing with new pharmacological approaches targeting the intricate mTOR network, such as dual PI3K/mTOR inhibitors and new-generation inhibitors (namely, mTOR-KIs), might be able to open new avenues in the treatment of renal diseases in which the impaired mTOR pathway plays a relevant pathological role. Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper. Authors’ Contributions
Flávio Reis and Rui Alves contributed equally to this work. Acknowledgments
The authors thank HealthyAging 2020 (Centro-01-0145-FEDER-000012) for the Sofia D. Viana post-doc grant (HealthyAging2020 – BID 1.3). This work was financed by the European Regional Development Fund (ERDF) through the Centro 2020 Regional Operational Programme: project CENTRO-01-0145-FEDER-000012-HealthyAging2020 and the COMPETE 2020 – Operational Programme for Competitiveness and Internationalisation and the Portuguese national funds via Fundação para a Ciência e a Tecnologia (FCT), I.P.: project POCI-01-0145-FEDER-007440, as well as by UID/NEU/04539/2013 (CNC.IBILI Consortium strategic project) and POCI-01-0145-FEDER-031712 (project 031712). References D. M. Sabatini, “Twenty-five years of mTOR: uncovering the link from nutrients to growth,” Proceedings of the National Academy of Sciences , vol. 114, no. 45, pp. 11818–11825, 2017. View at Publisher · View at Google Scholar · View at Scopus M. I. Chiu, H. Katz, and V. Berlin, “RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex,” Proceedings of the National Academy of Sciences , vol. 91, no. 26, pp. 12574–12578, 1994. View at Publisher · View at Google Scholar · View at Scopus E. J. Brown, M. W. Albers, T. Bum Shin et al., “A mammalian protein targeted by G1-arresting rapamycin-receptor complex,” Nature , vol. 369, no. 6483, pp. 756–758, 1994. View at Publisher · View at Google Scholar · View at Scopus C. Vezina, A. Kudelski, and S. N. Sehgal, “Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle,” The Journal of Antibiotics , vol. 28, no. 10, pp. 721–726, 1975. View at Publisher · View at Google Scholar · View at Scopus P. T. Bhaskar and N. Hay, “The two TORCs and Akt,” Developmental Cell , vol. 12, no. 4, pp. 487–502, 2007. View at Publisher · View at Google Scholar · View at Scopus N. J. Lench, R. Macadam, and A. F. Markham, “The human gene encoding FKBP-rapamycin associated protein (FRAP) maps to chromosomal band 1p36.2,” Human Genetics , vol. 99, no. 4, pp. 547–549, 1997. View at Publisher · View at Google Scholar · View at Scopus M. Laplante and D. M. Sabatini, “mTOR signaling,” Cold Spring Harbor Perspectives in Biology , vol. 4, no. 2, 2012. View at Publisher · View at Google Scholar · View at Scopus R. A. Saxton and D. M. Sabatini, “mTOR signaling in growth, metabolism, and disease,” Cell , vol. 168, no. 6, pp. 960–976, 2017. View at Publisher · View at Google Scholar · View at Scopus R. Zoncu, A. Efeyan, and D. M. Sabatini, “MTOR: from growth signal integration to cancer, diabetes and ageing,” Nature Reviews Molecular Cell Biology , vol. 12, no. 1, pp. 21–35, 2011. View at Publisher · View at Google Scholar · View at Scopus F. Palavra, C. Robalo, and F. Reis, “Recent advances and challenges of mTOR inhibitors use in the treatment of patients with tuberous sclerosis complex,” Oxidative Medicine and Cellular Longevity , vol. 2017, Article ID 9820181, 11 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus R. Fernandes and F. Reis, “mTOR in diabetic nephropathy and retinopathy,” in Molecules to Medicine with mTOR , pp. 379–393, Translating Critical Pathways into Novel Therapeutic Strategies, 2016. View at Publisher · View at Google Scholar · View at Scopus F. Palavra, A. F. Ambrósio, and F. Reis, “mTOR and neuroinflammation,” in Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies , pp. 317–329, Elsevier, 2016. View at Publisher · View at Google Scholar · View at Scopus D. W. Lamming, “Inhibition of the mechanistic target of rapamycin (mTOR)–rapamycin and beyond,” Cold Spring Harbor Perspectives in Medicine , vol. 6, no. 5, 2016. View at Publisher · View at Google Scholar · View at Scopus M. Laplante and D. M. Sabatini, “MTOR signaling in growth control and disease,” Cell , vol. 149, no. 2, pp. 274–293, 2012. View at Publisher · View at Google Scholar · View at Scopus L. Bar-Peled and D. M. Sabatini, “Regulation of mTORC1 by amino acids,” Trends in Cell Biology , vol. 24, no. 7, pp. 400–406, 2014. View at Publisher · View at Google Scholar · View at Scopus T. R. Peterson, S. S. Sengupta, T. E. Harris et al., “MTOR complex 1 regulates lipin 1 localization to control the SREBP pathway,” Cell , vol. 146, no. 3, pp. 408–420, 2011. View at Publisher · View at Google Scholar · View at Scopus A. Ichikawa, T. Nakahara, Y. Kurauchi, A. Mori, K. Sakamoto, and K. Ishii, “Rapamycin prevents N-methyl-D-aspartate-induced retinal damage through an ERK-dependent mechanism in rats,” Journal of Neuroscience Research , vol. 92, no. 6, pp. 692–702, 2014. View at Publisher · View at Google Scholar · View at Scopus V. Zinzalla, D. Stracka, W. Oppliger, and M. N. Hall, “Activation of mTORC2 by association with the ribosome,” Cell , vol. 144, no. 5, pp. 757–768, 2011. View at Publisher · View at Google Scholar · View at Scopus M. Ebner, B. Sinkovics, M. Szczygieł, D. W. Ribeiro, and I. Yudushkin, “Localization of mTORC2 activity inside cells,” The Journal of Cell Biology , vol. 216, no. 2, pp. 343–353, 2017. View at Publisher · View at Google Scholar · View at Scopus A. Parrales, E. López, I. Lee-Rivera, and A. M. López-Colomé, “ERK1/2-dependent activation of mTOR/mTORC1/p70S6K regulates thrombin-induced RPE cell proliferation,” Cellular Signalling , vol. 25, no. 4, pp. 829–838, 2013. View at Publisher · View at Google Scholar · View at Scopus Y. H. Bian, J. Xu, W. Y. Zhao et al., “Targeting mTORC2 component rictor inhibits cell proliferation and promotes apoptosis in gastric cancer,” American Journal of Translational Research , vol. 9, no. 9, pp. 4317–4330, 2017. View at Google Scholar I. S. Guimarães, N. G. Tessarollo, P. C. M. Lyra-Júnior et al., “Targeting the PI3K/AKT/mTOR pathway in cancer cells,” in Updates on Cancer Treatment , InTech, 2015. View at Publisher · View at Google Scholar M. Jhanwar-Uniyal, A. G. Amin, J. B. Cooper, K. Das, M. H. Schmidt, and R. Murali, “Discrete signaling mechanisms of mTORC1 and mTORC2: connected yet apart in cellular and molecular aspects,” Advances in Biological Regulation , vol. 64, pp. 39–48, 2017. View at Publisher · View at Google Scholar · View at Scopus P. Dalle Pezze, A. G. Sonntag, A. Thien et al., “A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation,” Science Signaling , vol. 5, no. 217, article ra25, 2012. View at Publisher · View at Google Scholar · View at Scopus A. M. Martelli, F. Buontempo, and J. A. McCubrey, “Drug discovery targeting the mTOR pathway,” Clinical Science , vol. 132, no. 5, pp. 543–568, 2018. View at Publisher · View at Google Scholar · View at Scopus J. Xie, X. Wang, and C. G. Proud, “mTOR inhibitors in cancer therapy,” F1000Research , vol. 5, p. 2078, 2016. View at Publisher · View at Google Scholar · View at Scopus A. Kurdi, G. R. Y. De Meyer, and W. Martinet, “Potential therapeutic effects of mTOR inhibition in atherosclerosis,” British Journal of Clinical Pharmacology , vol. 82, no. 5, pp. 1267–1279, 2015. View at Publisher · View at Google Scholar · View at Scopus K. Maiese, “Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders,” British Journal of Clinical Pharmacology , vol. 82, no. 5, pp. 1245–1266, 2016. View at Publisher · View at Google Scholar · View at Scopus C. Gaubitz, T. M. Oliveira, M. Prouteau et al., “Molecular basis of the rapamycin insensitivity of target of rapamycin complex 2,” Molecular Cell , vol. 58, no. 6, pp. 977–988, 2015. View at Publisher · View at Google Scholar · View at Scopus D. W. Lamming, L. Ye, P. Katajisto et al., “Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity,” Science , vol. 335, no. 6076, pp. 1638–1643, 2012. View at Publisher · View at Google Scholar · View at Scopus D. D. Sarbassov, S. M. Ali, S. Sengupta et al., “Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB,” Molecular Cell , vol. 22, no. 2, pp. 159–168, 2006. View at Publisher · View at Google Scholar · View at Scopus T. H. Kim, S. J. Choi, Y. H. Lee, G. G. Song, and J. D. Ji, “Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis,” Medical Hypotheses , vol. 79, no. 6, pp. 757–760, 2012. View at Publisher · View at Google Scholar · View at Scopus R. J. O. Dowling, I. Topisirovic, T. Alain et al., “mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs,” Science , vol. 328, no. 5982, pp. 1172–1176, 2010. View at Publisher · View at Google Scholar · View at Scopus C. K. Yip, K. Murata, T. Walz, D. M. Sabatini, and S. A. Kang, “Structure of the human mTOR complex I and its implications for rapamycin inhibition,” Molecular Cell , vol. 38, no. 5, pp. 768–774, 2010. View at Publisher · View at Google Scholar · View at Scopus D. M. Sabatini, H. Erdjument-Bromage, M. Lui, P. Tempst, and S. H. Snyder, “RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs,” Cell , vol. 78, no. 1, pp. 35–43, 1994. View at Publisher · View at Google Scholar · View at Scopus J. P. MacKeigan and D. A. Krueger, “Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex,” Neuro-Oncology , vol. 17, no. 12, pp. 1550–1559, 2015. View at Publisher · View at Google Scholar · View at Scopus M. J. Pereira, J. Palming, M. Rizell et al., “MTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes,” Molecular and Cellular Endocrinology , vol. 355, no. 1, pp. 96–105, 2012. View at Publisher · View at Google Scholar · View at Scopus S. Sivendran, N. Agarwal, B. Gartrell et al., “Metabolic complications with the use of mTOR inhibitors for cancer therapy,” Cancer Treatment Reviews , vol. 40, no. 1, pp. 190–196, 2014. View at Publisher · View at Google Scholar · View at Scopus B. Cheaib, A. Auguste, and A. Leary, “The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges,” Chinese Journal of Cancer , vol. 34, no. 1, pp. 4–16, 2015. View at Publisher · View at Google Scholar · View at Scopus F. Han, S. Lin, P. Liu et al., “Discovery of a novel series of thienopyrimidine as highly potent and selective PI3K inhibitors,” ACS Medicinal Chemistry Letter , vol. 6, no. 4, pp. 434–438, 2015. View at Publisher · View at Google Scholar · View at Scopus Q. W. Fan, C. K. Cheng, T. P. Nicolaides et al., “A dual phosphoinositide-3-kinase α /mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma,” Cancer Research , vol. 67, no. 17, pp. 7960–7965, 2007. View at Publisher · View at Google Scholar · View at Scopus F. I. Raynaud, S. Eccles, P. A. Clarke et al., “Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases,” Cancer Research , vol. 67, no. 12, pp. 5840–5850, 2007. View at Publisher · View at Google Scholar · View at Scopus L. Herschbein and J. L. Liesveld, “Dueling for dual inhibition: means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML,” Blood Reviews , vol. 32, no. 3, pp. 235–248, 2018. View at Publisher · View at Google Scholar · View at Scopus N. Chapuis, J. Tamburini, A. S. Green et al., “Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies,” Leukemia , vol. 24, no. 10, pp. 1686–1699, 2010. View at Publisher · View at Google Scholar · View at Scopus J. Tamburini, A. S. Green, V. Bardet et al., “Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia,” Blood , vol. 114, no. 8, pp. 1618–1627, 2009. View at Publisher · View at Google Scholar · View at Scopus B. Hassan, A. Akcakanat, T. Sangai et al., “Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors,” Oncotarget , vol. 5, no. 18, pp. 8544–8557, 2014. View at Publisher · View at Google Scholar · View at Scopus T. Vandamme, M. Beyens, K. O. de Beeck et al., “Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors,” British Journal of Cancer , vol. 114, no. 6, pp. 650–658, 2016. View at Publisher · View at Google Scholar · View at Scopus D. A. Guertin, D. M. Stevens, C. C. Thoreen et al., “Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC α , but not S6K1,” Developmental Cell , vol. 11, no. 6, pp. 859–871, 2006. View at Publisher · View at Google Scholar · View at Scopus L. R. Pearce, E. M. Sommer, K. Sakamoto, S. Wullschleger, and D. R. Alessi, “Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney,” Biochemical Journal , vol. 436, no. 1, pp. 169–179, 2011. View at Publisher · View at Google Scholar · View at Scopus V. S. Rodrik-Outmezguine, M. Okaniwa, Z. Yao et al., “Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor,” Nature , vol. 534, no. 7606, pp. 272–276, 2016. View at Publisher · View at Google Scholar · View at Scopus Q. W. Fan, O. Aksoy, R. A. Wong et al., “A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma,” Cancer Cell , vol. 31, no. 3, pp. 424–435, 2017. View at Publisher · View at Google Scholar · View at Scopus Q. W. Fan, T. P. Nicolaides, and W. A. Weiss, “Inhibiting 4EBP1 in glioblastoma,” Clinical Cancer Research , vol. 24, no. 1, pp. 14–21, 2018. View at Publisher · View at Google Scholar · View at Scopus N. Morisot, C. J. Novotny, K. M. Shokat, and D. Ron, “A new generation of mTORC1 inhibitor attenuates alcohol intake and reward in mice,” Addiction Biology , vol. 23, no. 2, pp. 713–722, 2018. View at Publisher · View at Google Scholar · View at Scopus F. Grahammer, N. Wanner, and T. B. Huber, “mTOR controls kidney epithelia in health and disease,” Nephrology Dialysis Transplantation , vol. 29, Supplement 1, pp. i9–i18, 2014. View at Publisher · View at Google Scholar · View at Scopus F. Grahammer, N. Wanner, and T. B. Huber, “Podocyte regeneration: who can become a podocyte?” American Journal of Pathology , vol. 183, no. 2, pp. 333–335, 2013. View at Publisher · View at Google Scholar · View at Scopus J.-K. Guo, A. Marlier, H. Shi et al., “Increased tubular proliferation as an adaptive response to glomerular albuminuria,” Journal of the American Society of Nephrology , vol. 23, no. 3, pp. 429–437, 2012. View at Publisher · View at Google Scholar · View at Scopus K. Inoki and T. B. Huber, “Mammalian target of rapamycin signaling in the podocyte,” Current Opinion in Nephrology and Hypertension , vol. 21, no. 3, pp. 251–257, 2012. View at Publisher · View at Google Scholar · View at Scopus M. Gödel, B. Hartleben, N. Herbach et al., “Role of mTOR in podocyte function and diabetic nephropathy in humans and mice,” The Journal of Clinical Investigation , vol. 121, no. 6, pp. 2197–2209, 2011. View at Publisher · View at Google Scholar · View at Scopus H. Amer and F. G. Cosio, “Significance and management of proteinuria in kidney transplant recipients,” Journal of the American Society of Nephrology , vol. 20, no. 12, pp. 2490–2492, 2009. View at Publisher · View at Google Scholar · View at Scopus J. Torras, I. Herrero-Fresneda, O. Gulias et al., “Rapamycin has dual opposing effects on proteinuric experimental nephropathies: is it a matter of podocyte damage,” Nephrology Dialysis Transplantation , vol. 24, no. 12, pp. 3632–3640, 2009. View at Publisher · View at Google Scholar · View at Scopus J. Sereno, B. Parada, P. Rodrigues-Santos et al., “Serum and renal tissue markers of nephropathy in rats under immunosuppressive therapy: cyclosporine versus sirolimus,” Transplantation Proceedings , vol. 45, no. 3, pp. 1149–1156, 2013. View at Publisher · View at Google Scholar · View at Scopus J. Sereno, S. Nunes, P. Rodrigues-Santos et al., “Conversion to sirolimus ameliorates cyclosporine-induced nephropathy in the rat: focus on serum, urine, gene, and protein renal expression biomarkers,” BioMed Research International , vol. 2014, Article ID 576929, 17 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus J. Sereno, H. Vala, S. Nunes et al., “Cyclosporine a-induced nephrotoxicity is ameliorated by dose reduction and conversion to sirolimus in the rat,” Journal of Physiology and Pharmacology , vol. 66, no. 2, pp. 285–299, 2015. View at Google Scholar G. Canaud, F. Bienaimé, A. Viau et al., “AKT2 is essential to maintain podocyte viability and function during chronic kidney disease,” Nature Medicine , vol. 19, no. 10, pp. 1288–1296, 2013. View at Publisher · View at Google Scholar · View at Scopus M. Haller, S. Amatschek, J. Wilflingseder et al., “Sirolimus induced phosphaturia is not caused by inhibition of renal apical sodium phosphate cotransporters,” PLoS One , vol. 7, no. 7, article e39229, 2012. View at Publisher · View at Google Scholar · View at Scopus M. Lu, J. Wang, H. E. Ives, and D. Pearce, “mSIN1 protein mediates SGK1 protein interaction with mTORC2 protein complex and is required for selective activation of the epithelial sodium channel,” Journal of Biological Chemistry , vol. 286, no. 35, pp. 30647–30654, 2011. View at Publisher · View at Google Scholar · View at Scopus H. Ekberg, H. Tedesco-Silva, A. Demirbas et al., “Reduced exposure to calcineurin inhibitors in renal transplantation,” New England Journal of Medicine , vol. 357, no. 25, pp. 2562–2575, 2007. View at Publisher · View at Google Scholar · View at Scopus J. Sellarés, D. G. de Freitas, M. Mengel et al., “Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence,” American Journal of Transplantation , vol. 12, no. 2, pp. 388–399, 2012. View at Publisher · View at Google Scholar · View at Scopus B. D. Kahan, “Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study,” The Lancet , vol. 356, no. 9225, pp. 194–202, 2000. View at Publisher · View at Google Scholar · View at Scopus B. D. Kahan, “Two-year results of multicenter phase III trials on the effect of the addition of sirolimus to cyclosporine-based immunosuppressive regimens in renal transplantation,” Transplantation Proceedings , vol. 35, no. 3, pp. S37–S51, 2003. View at Publisher · View at Google Scholar · View at Scopus S. M. Flechner, M. Glyda, S. Cockfield et al., “The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients,” American Journal of Transplantation , vol. 11, no. 8, pp. 1633–1644, 2011. View at Publisher · View at Google Scholar · View at Scopus S. M. Flechner, D. Goldfarb, K. Solez et al., “Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs,” Transplantation , vol. 83, no. 7, pp. 883–892, 2007. View at Publisher · View at Google Scholar · View at Scopus Y. Lebranchu, R. Snanoudj, O. Toupance et al., “Five-year results of a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation: the Spiesser study,” American Journal of Transplantation , vol. 12, no. 7, pp. 1801–1810, 2012. View at Publisher · View at Google Scholar · View at Scopus Y. Lebranchu, A. Thierry, O. Toupance et al., “Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study,” American Journal of Transplantation , vol. 9, no. 5, pp. 1115–1123, 2009. View at Publisher · View at Google Scholar · View at Scopus K. Budde, T. Becker, W. Arns et al., “Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial,” The Lancet , vol. 377, no. 9768, pp. 837–847, 2011. View at Publisher · View at Google Scholar · View at Scopus K. Budde, F. Lehner, C. Sommerer et al., “Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study,” American Journal of Transplantation , vol. 15, no. 1, pp. 119–128, 2015. View at Publisher · View at Google Scholar · View at Scopus M. R. Weir, S. Mulgaonkar, L. Chan et al., “Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled spare-the-nephron trial,” Kidney International , vol. 79, no. 8, pp. 897–907, 2011. View at Publisher · View at Google Scholar · View at Scopus L. Liefeldt, S. Brakemeier, P. Glander et al., “Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation,” American Journal of Transplantation , vol. 12, no. 5, pp. 1192–1198, 2012. View at Publisher · View at Google Scholar · View at Scopus B. D. Kahan, J. Podbielski, K. L. Napoli, S. M. Katz, H. U. Meier-Kriesche, and C. T. van Buren, “Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation,” Transplantation , vol. 66, no. 8, pp. 1040–1046, 1998. View at Publisher · View at Google Scholar · View at Scopus G. Ciancio, G. W. Burke, J. J. Gaynor et al., “A randomized long-term trial of tacrolimus/sirolimus versus tacrolimums/mycophenolate versus cyclosporine/sirolimus in renal transplantation: three-year analysis,” Transplantation , vol. 81, no. 6, pp. 845–852, 2006. View at Publisher · View at Google Scholar · View at Scopus R. M. Langer, R. Hené, S. Vitko et al., “Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation,” Transplant International , vol. 25, no. 5, pp. 592–602, 2012. View at Publisher · View at Google Scholar · View at Scopus G. R. Russ, S. Campbell, S. Chadban et al., “Reduced and standard target concentration tacrolimus with sirolimus in renal allograft recipients,” Transplantation Proceedings , vol. 35, no. 3, pp. S115–S117, 2003. View at Publisher · View at Google Scholar · View at Scopus V. R. Peddi, A. Wiseman, K. Chavin, and D. Slakey, “Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation,” Transplantation Reviews , vol. 27, no. 4, pp. 97–107, 2013. View at Publisher · View at Google Scholar · View at Scopus J. Pascual, T. Srinivas, S. Chadban et al., “TRANSFORM: a novel study design to evaluate the effect of everolimus on long-term outcomes after kidney transplantation,” Open Access Journal of Clinical Trials , vol. 6, pp. 45–53, 2014. View at Publisher · View at Google Scholar · View at Scopus “Best abstract challenge,” Transplant International , vol. 30, pp. 5–7, 2017. View at Publisher · View at Google Scholar A. Cordido, L. Besada-Cerecedo, and M. A. García-González, “The genetic and cellular basis of autosomal dominant polycystic kidney disease—a primer for clinicians,” Frontiers in Pediatrics , vol. 5, 2017. View at Publisher · View at Google Scholar · View at Scopus C. Bergmann, “Genetics of autosomal recessive polycystic kidney disease and its differential diagnoses,” Frontiers in Pediatrics , vol. 5, 2018. View at Publisher · View at Google Scholar J. Reiterová, J. Štekrová, M. Merta et al., “Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele,” BMC Nephrology , vol. 14, no. 1, 2013. View at Publisher · View at Google Scholar · View at Scopus W. Lieberthal and J. S. Levine, “The role of the mammalian target of rapamycin (mTOR) in renal disease,” Journal of the American Society of Nephrology , vol. 20, no. 12, pp. 2493–2502, 2009. View at Publisher · View at Google Scholar · View at Scopus E. Cornec-Le Gall, V. E. Torres, and P. C. Harris, “Genetic complexity of autosomal dominant polycystic kidney and liver diseases,” Journal of the American Society of Nephrology , vol. 29, no. 1, pp. 13–23, 2017. View at Publisher · View at Google Scholar · View at Scopus P. A. Gabow, “Autosomal dominant polycystic kidney disease,” New England Journal of Medicine , vol. 329, no. 5, pp. 332–342, 1993. View at Publisher · View at Google Scholar · View at Scopus J. J. Grantham, V. E. Torres, A. B. Chapman et al., “Volume progression in polycystic kidney disease,” New England Journal of Medicine , vol. 354, no. 20, pp. 2122–2130, 2006. View at Publisher · View at Google Scholar · View at Scopus The International Polycystic Kidney Disease Consortium, “Polycystic kidney disease: the complete structure of the PKD1 gene and its protein,” Cell , vol. 81, no. 2, pp. 289–298, 1995. View at Publisher · View at Google Scholar · View at Scopus T. Mochizuki, G. Wu, T. Hayashi et al., “PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein,” Science , vol. 272, no. 5266, pp. 1339–1342, 1996. View at Publisher · View at Google Scholar · View at Scopus A. C. M. Ong and P. C. Harris, “Molecular pathogenesis of ADPKD: the polycystin complex gets complex,” Kidney International , vol. 67, no. 4, pp. 1234–1247, 2005. View at Publisher · View at Google Scholar · View at Scopus N. N. Zheleznova, P. D. Wilson, and A. Staruschenko, “Epidermal growth factor-mediated proliferation and sodium transport in normal and PKD epithelial cells,” Biochimica et Biophysica Acta-Molecular Basis of Disease , vol. 1812, no. 10, pp. 1301–1313, 2011. View at Publisher · View at Google Scholar · View at Scopus F. A. Belibi, G. Reif, D. P. Wallace et al., “Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells,” Kidney International , vol. 66, no. 3, pp. 964–973, 2004. View at Publisher · View at Google Scholar · View at Scopus J. M. Shillingford, N. S. Murcia, C. H. Larson et al., “The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease,” Proceedings of the National Academy of Sciences , vol. 103, no. 14, pp. 5466–5471, 2006. View at Publisher · View at Google Scholar · View at Scopus P. T. Brook-Carter, B. Peral, C. J. Ward et al., “Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease — a contiguous gene syndrome,” Nature Genetics , vol. 8, no. 4, pp. 328–332, 1994. View at Publisher · View at Google Scholar · View at Scopus Y. Tao, J. Kim, R. W. Schrier, and C. L. Edelstein, “Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease,” Journal of the American Society of Nephrology , vol. 16, no. 1, pp. 46–51, 2004. View at Publisher · View at Google Scholar · View at Scopus V. H. Gattone II, R. M. Sinders, T. A. Hornberger, and A. G. Robling, “Late progression of renal pathology and cyst enlargement is reduced by rapamycin in a mouse model of nephronophthisis,” Kidney International , vol. 76, no. 2, pp. 178–182, 2009. View at Publisher · View at Google Scholar · View at Scopus P. R. Wahl, A. L. Serra, M. le Hir, K. D. Molle, M. N. Hall, and R. P. Wüthrich, “Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD),” Nephrology Dialysis Transplantation , vol. 21, no. 3, pp. 598–604, 2006. View at Publisher · View at Google Scholar · View at Scopus T. Zhang, L. Wang, X. Xiong, Z. Mao, L. Wang, and C. Mei, “Mycophenolate mofetil versus rapamycin in Han: SPRD rats with polycystic kidney disease,” Biological Research , vol. 42, no. 4, pp. 437–444, 2009. View at Publisher · View at Google Scholar · View at Scopus O. Ibraghimov-Beskrovnaya and T. A. Natoli, “MTOR signaling in polycystic kidney disease,” Trends in Molecular Medicine , vol. 17, no. 11, pp. 625–633, 2011. View at Publisher · View at Google Scholar · View at Scopus C. Renken, D. C. Fischer, G. Kundt, N. Gretz, and D. Haffner, “Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats,” Nephrology, Dialysis, Transplantation , vol. 26, no. 1, pp. 92–100, 2010. View at Publisher · View at Google Scholar · View at Scopus A. Li, S. Fan, Y. Xu et al., “Rapamycin treatment dose-dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell-cycle-associated CDK1/cyclin axis,” Journal of Cellular and Molecular Medicine , vol. 21, no. 8, pp. 1619–1635, 2017. View at Publisher · View at Google Scholar · View at Scopus I. Zafar, K. Ravichandran, F. A. Belibi, R. B. Doctor, and C. L. Edelstein, “Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease,” Kidney International , vol. 78, no. 8, pp. 754–761, 2010. View at Publisher · View at Google Scholar · View at Scopus T. H. Booij, H. Bange, W. N. Leonhard et al., “High-throughput phenotypic screening of kinase inhibitors to identify drug targets for polycystic kidney disease,” SLAS DISCOVERY: Advancing Life Sciences R&D , vol. 22, no. 8, pp. 974–984, 2017. View at Publisher · View at Google Scholar · View at Scopus K. Ravichandran, I. Zafar, A. Ozkok, and C. L. Edelstein, “An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease,” Nephrology, Dialysis, Transplantation , vol. 30, no. 1, pp. 45–53, 2015. View at Publisher · View at Google Scholar · View at Scopus Z. Novalic, A. M. van der Wal, W. N. Leonhard et al., “Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease,” Journal of the American Society of Nephrology , vol. 23, no. 5, pp. 842–853, 2012. View at Publisher · View at Google Scholar · View at Scopus A. L. Serra, D. Poster, A. D. Kistler et al., “Sirolimus and kidney growth in autosomal dominant polycystic kidney disease,” The New England Journal of Medicine , vol. 363, no. 9, pp. 820–829, 2010. View at Publisher · View at Google Scholar · View at Scopus N. Perico, L. Antiga, A. Caroli et al., “Sirolimus therapy to halt the progression of ADPKD,” Journal of the American Society of Nephrology , vol. 21, no. 6, pp. 1031–1040, 2010. View at Publisher · View at Google Scholar · View at Scopus G. Walz, K. Budde, M. Mannaa et al., “Everolimus in patients with autosomal dominant polycystic kidney disease,” New England Journal of Medicine , vol. 363, no. 9, pp. 830–840, 2010. View at Publisher · View at Google Scholar · View at Scopus G. Stallone, B. Infante, G. Grandaliano et al., “Rapamycin for treatment of type I autosomal dominant polycystic kidney disease (RAPYD-study): a randomized, controlled study,” Nephrology Dialysis Transplantation , vol. 27, no. 9, pp. 3560–3567, 2012. View at Publisher · View at Google Scholar · View at Scopus Q. Qian, H. du, B. F. King et al., “Sirolimus reduces polycystic liver volume in ADPKD patients,” Journal of the American Society of Nephrology , vol. 19, no. 3, pp. 631–638, 2008. View at Publisher · View at Google Scholar · View at Scopus D. Bolignano, S. C. Palmer, M. Ruospo et al., “Interventions for preventing the progression of autosomal dominant polycystic kidney disease,” Cochrane Database of Systematic Reviews , vol. 7, 2015. View at Publisher · View at Google Scholar · View at Scopus J. J. Grantham, S. Mulamalla, and K. I. Swenson-Fields, “Why kidneys fail in autosomal dominant polycystic kidney disease,” Nature Reviews Nephrology , vol. 7, no. 10, pp. 556–566, 2011. View at Publisher · View at Google Scholar · View at Scopus Q. He, C. Lin, S. Ji, and J. Chen, “Efficacy and safety of mTOR inhibitor therapy in patients with early-stage autosomal dominant polycystic kidney disease: a meta-analysis of randomized controlled trials,” The American Journal of the Medical Sciences , vol. 344, no. 6, pp. 491–497, 2012. View at Publisher · View at Google Scholar · View at Scopus G. Canaud, B. Knebelmann, P. C. Harris et al., “Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: what is the appropriate serum level?” American Journal of Transplantation , vol. 10, no. 7, pp. 1701–1706, 2010. View at Publisher · View at Google Scholar · View at Scopus T. Saigusa and P. D. Bell, “Molecular pathways and therapies in autosomal-dominant polycystic kidney disease,” Physiology , vol. 30, no. 3, pp. 195–207, 2015. View at Publisher · View at Google Scholar · View at Scopus M. E. Feldman, B. Apsel, A. Uotila et al., “Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2,” PLoS Biology , vol. 7, no. 2, article e38, 2009. View at Publisher · View at Google Scholar · View at Scopus M. Kajiwara and S. Masuda, “Role of mTOR inhibitors in kidney disease,” International Journal of Molecular Sciences , vol. 17, no. 6, 2016. View at Publisher · View at Google Scholar · View at Scopus The Cancer Genome Atlas Research Network, “Comprehensive molecular characterization of clear cell renal cell carcinoma,” Nature , vol. 499, no. 7456, pp. 43–49, 2013. View at Publisher · View at Google Scholar · View at Scopus M. Song, “Recent developments in small molecule therapies for renal cell carcinoma,” European Journal of Medicinal Chemistry , vol. 142, pp. 383–392, 2017. View at Publisher · View at Google Scholar · View at Scopus H. L. Kenerson, L. D. Aicher, L. D. True, and R. S. Yeung, “Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors,” Cancer Research , vol. 62, no. 20, pp. 5645–5650, 2002. View at Google Scholar J. B. Brugarolas, F. Vazquez, A. Reddy, W. R. Sellers, and W. G. Kaelin Jr, “TSC2 regulates VEGF through mTOR-dependent and -independent pathways,” Cancer Cell , vol. 4, no. 2, pp. 147–158, 2003. View at Publisher · View at Google Scholar · View at Scopus H. D. Husseinzadeh and J. A. Garcia, “Therapeutic rationale for mTOR inhibition in advanced renal cell carcinoma,” Current Clinical Pharmacology , vol. 6, no. 3, pp. 214–221, 2011. View at Publisher · View at Google Scholar · View at Scopus D. Fantus, N. M. Rogers, F. Grahammer, T. B. Huber, and A. W. Thomson, “Roles of mTOR complexes in the kidney: implications for renal disease and transplantation,” Nature Reviews Nephrology , vol. 12, no. 10, pp. 587–609, 2016. View at Publisher · View at Google Scholar · View at Scopus T. Lin, C. Leung, K. Nguyen, and R. A. Figlin, “Mammalian target of rapamycin (mTOR) inhibitors in solid tumours,” Clinical Pharmacist , vol. 8, 2016. View at Publisher · View at Google Scholar · View at Scopus S. K. Pal and D. I. Quinn, “Differentiating mTOR inhibitors in renal cell carcinoma,” Cancer Treatment Reviews , vol. 39, no. 7, pp. 709–719, 2013. View at Publisher · View at Google Scholar · View at Scopus T. K. Choueiri, B. Escudier, T. Powles et al., “Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial,” The Lancet Oncology , vol. 17, no. 7, pp. 917–927, 2016. View at Publisher · View at Google Scholar · View at Scopus D. Cella, V. Grünwald, P. Nathan et al., “Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial,” The Lancet Oncology , vol. 17, no. 7, pp. 994–1003, 2016. View at Publisher · View at Google Scholar · View at Scopus A. A. Elfiky, S. A. Aziz, P. J. Conrad et al., “Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer,” Journal of Translational Medicine , vol. 9, no. 1, p. 133, 2011. View at Publisher · View at Google Scholar · View at Scopus D. C. Cho, M. B. Cohen, D. J. Panka et al., “The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma,” Clinical Cancer Research , vol. 16, pp. 3628–3638, 2010. View at Google Scholar B. Zheng, J. H. Mao, L. Qian et al., “Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma,” Cancer Letters , vol. 357, no. 2, pp. 468–475, 2015. View at Publisher · View at Google Scholar · View at Scopus T. Powles, M. Wheater, O. Din et al., “A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer,” European Urology , vol. 69, no. 3, pp. 450–456, 2016. View at Publisher · View at Google Scholar · View at Scopus Z. Xiong, Y. Zang, S. Zhong et al., “The preclinical assessment of XL388, a mTOR kinase inhibitor, as a promising anti-renal cell carcinoma agent,” Oncotarget , vol. 8, no. 18, pp. 30151–30161, 2017. View at Publisher · View at Google Scholar · View at Scopus A. A. Soukas, E. A. Kane, C. E. Carr, J. A. Melo, and G. Ruvkun, “Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans,” Genes & Development , vol. 23, no. 4, pp. 496–511, 2009. View at Publisher · View at Google Scholar · View at Scopus H. H. Zhang, J. Huang, K. Düvel et al., “Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway,” PLoS One , vol. 4, no. 7, article e6189, 2009. View at Publisher · View at Google Scholar · View at Scopus V. P. Houde, S. Brule, W. T. Festuccia et al., “Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue,” Diabetes , vol. 59, no. 6, pp. 1338–1348, 2010. View at Publisher · View at Google Scholar · View at Scopus M.-J. Lee, D. Feliers, M. M. Mariappan et al., “A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy,” American Journal of Physiology-Renal Physiology , vol. 292, no. 2, pp. F617–F627, 2007. View at Publisher · View at Google Scholar · View at Scopus M. Sakaguchi, M. Isono, K. Isshiki, T. Sugimoto, D. Koya, and A. Kashiwagi, “Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice,” Biochemical and Biophysical Research Communications , vol. 340, no. 1, pp. 296–301, 2006. View at Publisher · View at Google Scholar · View at Scopus K. Inoki, H. Mori, J. Wang et al., “mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice,” Journal of Clinical Investigation , vol. 121, no. 6, pp. 2181–2196, 2011. View at Publisher · View at Google Scholar · View at Scopus F. Reis, B. Parada, E. Teixeira de Lemos et al., “H

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Emsam is indicated for the treatment of major depressive disorder.
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Use Emsam exactly as directed on the label, or as it has been prescribed by your doctor. Do not use more than recommended. Follow the directions on your prescription label.
For patients using Emsam: While you are using Emsam and for 14 days after you stop, you must not eat foods high in tyramine (listed in the “What should I avoid?” section of this leaflet. Eating these foods while you are taking Emsam can raise your blood pressure to dangerous levels.
Foods that you MAY eat include:
fresh meat, poultry, or fish (including lunch meat, hot dogs, breakfast sausage, and cooked sliced ham);
any vegetables except broad bean pods (fava beans);
processed cheese, mozzarella, ricotta, cottage cheese;
pizza made with cheeses low in tyramine;
soy milk, yogurt; or
Brewer’s or baker’s yeast.
This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.
Do not stop using Emsam suddenly or you may have harmful side effects. It may take several weeks of using Emsam before your symptoms improve. For best results, keep using the medication as directed. Store Emsam at room temperature away from heat and moisture.
If you missed a dose – take it as soon as you remember. If it is almost time to take the next pill, skip the missed dose and take the medication at your next regularly scheduled time. Do not take extra pills to make up the missed dose.
DOSAGE
The recommended starting dose and target dose for Emsam (selegiline transdermal system) is 6 mg/24 hours.
STORAGE
Store Emsam at 20º to 25º C (68º to 77º F).[See USP Controlled Room Temperature.] Keep away from children, pets or others.
SAFETY INFORMATION
Do not use Emsam if you are allergic to selegiline, if you have an adrenal gland tumor (also called pheochromocytoma), or if you plan to have any type of surgery. Do not use Emsam if you have taken any of the following drugs within the past 14 days:
buspirone (BuSpar);
carbamazepine (Tegretol) or oxcarbazepine (Trileptal);
cyclobenzaprine (Flexeril);
dextromethorphan (cough medicine);
meperidine (Demerol), methadone (Dolophine, Methadose), propoxyphene (Darvon, Darvocet), or tramadol (Ultram, Ultracet);
mirtazapine (Remeron);
diet pills, ADHD medications, or cold medicines that contain dextromethorphan, ephedrine, pseudoephedrine, or phenylephrine;
St. John’s wort;
antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), bupropion (Wellbutrin, Zyban), citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), imipramine (Tofranil), nortriptyline (Pamelor), paroxetine (Paxil), protriptyline (Vivactil), sertraline (Zoloft), venlafaxine (Effexor), or trimipramine (Surmontil); or
other MAO inhibitors such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), rasagiline (Azilect), or oral selegiline (Eldepryl).
After you stop using Emsam, you must wait at least 14 days before taking any of the medications listed above.You must wait at least 5 weeks after stopping fluoxetine (Prozac) before you can start using Emsam.
Tell your doctor if you are allergic to any drugs, or if you have:
heart disease, high or low blood pressure;
seizures or epilepsy; or
a personal or family history of bipolar disorder (manic depression) or suicide attempt.
You may have thoughts about suicide when you first start using an antidepressant, especially if you are younger than 24 years old. Tell your doctor if you have worsening symptoms of depression or suicidal thoughts during the first several weeks of treatment, or whenever your dose is changed.
Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.
FDA pregnancy category C. Emsam may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether Emsam passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.
SIDE EFFECTS
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.
Stop using Emsam and call your doctor at once if you have any of these serious side effects:
sudden and severe headache, confusion, blurred vision, problems with speech or balance, nausea, vomiting, chest pain, seizure (convulsions), and sudden numbness or weakness (especially on one side of the body);
feeling light-headed, fainting;
twitching muscle movements; or
painful or difficult urination.
Less serious side effects may include:
constipation, gas, loss of appetite;
swelling, numbness or tingling, easy bruising, muscle pain;
dry mouth, sore throat, cough;
redness or itching where the patch is worn; or
impotence, loss of interest in sex, or trouble having an orgasm.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.
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The “boost” idea sounds good. I wonder how many have wanted or needed that… or how many may be slipping without knowing about a booster. As for you MIL, how long ago did she have TMS, and is she still with us? Just curious. Being the skeptic that I am, I probably wouldn’t go for this until there have been a few hundred thousand trailblazers ahead of me. But if it is really that good, I can see where millions of people will benefit from it.
How are you doing since your recent RP? It’s a bit strange to see RP a year after starting HT… but it’s good that the protocol you’re on seems to be working. Whopping PSA you had there. As another G8 I always feel so grateful that mine was addressed before it had spread any further. Good luck going forward.
Coincidence that you mentioned prednisone, as it was a fairly high dose of prednisone that really messed me up a few months ago. But it prompted my GP to order a CT, which in the end identified this abdominal mass that is being excised on Monday. Were it not for the chance Rx for 60mg of the steroid, I likely would not have known about the tumor until maybe a bowel obstruction… or possibly worse. Unfortunately the surgery required several months of tapering off of not only prednisone but also the Effexor, due to its short half life.
So by “unbalanced” do you mean emotionally/mentally? Mine was purely physical… extreme hot flashes (far more than HT) with profuse sweating, and some joint swelling, which puzzled the doctor.

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