Steph’s Note: We here at tl;dr aren’t (totally) oblivious. We know we’ve had a GIANT hole in a HUGE pharmacotherapy topic for years now: solid organ transplant (SOT). It’s a topic that deserves some serious justice and attention, but none of us here is exactly a transplant expert…and we didn’t have any brave volunteers who wanted to tackle this.

Until now.

We are so excited to introduce y’all to Michael Ball, PharmD. This courageous soul reached out to us wanting to write a post on SOT, and admittedly, we positively swooned. Dr. Ball graduated from pharmacy school at the University of Colorado in 2018. Afterwards, he completed a PGY1 residency at Presbyterian/St. Luke's Medical Center and the Rocky Mountain Hospital for Children, followed by a PGY2 in Solid Organ Transplant at Children's Healthcare of Atlanta. He moved back to Denver to work at his current position with Presbyterian/St. Luke’s as a clinical pharmacy specialist with their liver and kidney transplant teams. He loves transplant because of the autonomy and patient interaction that he gets to have on a daily basis. He’s lived in Colorado now for ~7 years and considers it home, although he grew up in Michigan (and says that Midwestern accent still pops up occasionally). In his downtime, he and his wife love taking their dog (George) to parks and on hikes.

“One or two?”

Nope, this isn’t an eye test. That’s the answer I get from students and residents when I ask them how many lectures they had on transplant topics. If I’m lucky.

This is poor transplant pharmacy… always getting shoved in the smallest bedroom (under the stairs). (Image)

Transplant has gotten the short end of the stick for a long time in pharmacy education. Even NAPLEX prep books treat it like Harry when Uncle Vernon has guests over.

Why? Well, transplant is complicated, and the patients are sort of siloed into their respective centers. Internal medicine teams groan. Pharmacists sweat at the sight of a tacrolimus level. But transplant is important to know!

Not only is pharmacy finally getting our own transplant Board Specialty Certification this year (yay!), but for 2021 alone, the UNOS website reported ~17,000 transplants when I started outlining this post (6/28/2021). This was up to ~21,000 by the time I completed it (7/27/21)! Small potatoes compared to hypertension or diabetes, but you will encounter transplant patients in the wilds of pharmacy.

Let’s not leave your comfort up to that 1 hour of lecture you got.

In this post, we’re going to focus on the common immunosuppressive agents for transplant patients. This is really the tip of the iceberg in terms of medications involved in transplant. As you’ll see though, these medications are complicated enough to start with.

I do want to be upfront in that I can write about transplant, but there’s no one way to do transplant (just like all medicine). The field is still in its adolescence and things aren’t perfect. Our toolbox of medications is pretty limited, and it’s been a while since we had some new snazzy drugs. That said, the tools we do have are pretty well loved, studied, and get different mileage depending on where you are.

Before we get into the drugs, we need to talk about what the heck transplant is and how we got here.

The Basics of Organ Transplant

Transplant can refer to two different areas: hematopoietic stem cell transplant (a.k.a. “bone marrow transplant”) and solid organ transplant (vascular organs). We’re referring to the non-liquid organs today, which most commonly include kidney, liver, heart, lung, and pancreas; but also small bowel, uterus, and vascular composite grafts (i.e., faces and more). We can also transplant things like corneas, but that’s also not the focus of today.

Here’s some of the common conditions behind the ‘big four’ organs being transplanted (not all inclusive):

These days, most people are familiar with the concept of transplant, but believe it or not, we haven’t been doing this that long. The first experiments with transplant weren’t all that promising - success was more proof-of-concept in that patients lasted hours to days after the surgery. The first real success with transplant was in 1954, when a kidney transplant was performed between identical twins.

It’s mind boggling to think about how far we’ve come though, in such a relatively short time! Your grandparents wouldn’t have had the option for a sustainable transplant until around the time humans went to the moon...and that’s all because of a little thing called the immune system.

Your immune system is really good at finding things that don’t belong. In the case of a virus or bacteria, that’s great news, but for your new heart, not so much. Preventing your immune system from starting all out warfare on your new organ is one of the primary goals of transplant medicine. To that effect, we use immunosuppression to prevent rejection of the organ. Steph’s recent post provides an excellent primer on immunology basics, which I highly recommend reviewing.

The complete mechanisms of rejection in transplant are very complicated, so let’s do a quick overview before we get started.

Everyone has a baseline risk of rejection we try to estimate. This estimation is spurred by previous exposure to foreign human things (e.g., previous transplants, pregnancy, blood transfusions). The more exposure, the broader and stronger of a threat your immune system can be. We need to check these antibodies before listing patients for transplant to know the baseline risk and what we should NOT put in your body. There’s a couple common ways we look at this:

First is the panel reactive antibody (PRA), which is reported as a percentage. This percentage represents the amount of human leukocyte antigens (HLA) you have active antibodies against. The higher percentage, the more HLA types from other people you would react to and the more limited your pool of potential donors would be. Think of this as if you opened a dating app profile, but only wanted to date people that have brown hair. Your pool of people is still pretty big, but you would reject a decent portion of the population.
Second are donor specific antibodies (DSA), which are determined via the HLA typing of the donor and your baseline antibodies. In general, we avoid transplanting an organ into a person that has a DSA against that organ. This would be like your mom setting you up on a date with a blond haired person knowing you’re not into that.

The innate immune system is involved with this process through a couple different ways mainly. First, the organ can get ischemia reperfusion injury once blood flow is reestablished after its time on ice. Complement gets involved here and helps facilitate a lot of inflammatory processes.

The adaptive immune system is a more constant threat, and we need to keep the new organ safe by hindering the immune system’s ability to recognize, respond, and mount an attack. A transplanted organ comes with some donor antigen presenting cells (namely dendritic cells), which can snitch on the new organ by telling the immune system it’s there.

Small bowel and lung transplants tend to be the highest risk for this due to the amount of lymphoid tissue coming with the organ. Aside from this, your body is constantly patrolling for interesting things to show your T cells via antigen presenting cells. This can trigger the activation of T cells, inflammatory attack on the organ, and subsequent development of antibodies to your organ. No bueno.

To recap T cell activation from an antigen presenting cell, let’s walk through the figure above (adapted from here). Antigen presenting cells (APC), well, present an antigen via MHC to the T helper cells T cell receptor (signal 1). This presentation isn’t enough though and it requires a costimulatory signal with B7 from the APC interacting with CD28 (signal 2). This process activates calcineurin which goes on to stimulate production of the cytokine IL-2, which self-stimulates the T helper cell (signal 3). The result of this is mTOR activates the cell cycle which leads to T cell differentiation into an effector T cell and also proliferation.

Pharmacotherapy of Induction Immunosuppression

When an organ gets transplanted, one of the first steps is to knock down the recipient’s immune system to prevent acute rejection of the organ. This varies with intensity and agent choice based on the transplant organ type, center, and baseline immunologic risk of the recipient and donor. The benefits of preventing acute rejection are increased long-term survival, but this isn’t without trade-offs, mainly higher infectious risk. Additionally, induction therapy allows us to start maintenance immunosuppression a little later, and use lower overall intensity.

Corticosteroids

Yep, good ole corticosteroids have a place here. When talking about induction though, we’re talking big kid dosing up front (i.e., 500-1000 mg of methylprednisolone) and then tapered. There’s really no standardized regimen for this, and it varies widely by organ type and center. At some places and for some organs, corticosteroids are sometimes used alone for transplant induction. Most commonly though, these are coupled with one of the following agents.

For such a common drug, how exactly corticosteroids work is a big conversation. Think of these as potentially lymphotoxic at high doses and an overall anti-cytokine/inflammatory bomb.

The adverse effects of corticosteroids are numerous and should be pretty familiar. We’ll get to this when we talk about maintenance corticosteroids, but specifically for the acute high dosing of corticosteroids, think insomnia, hyperglycemia, hypertension, and agitation.

Basiliximab (Simulect®)

Basiliximab is a non-lymphocyte depleting (chimeric “-xi-”) monoclonal antibody induction agent. It works by competitively inhibiting lymphocyte activation via IL-2.

Basiliximab is generally used for low-immunologic risk patients and is an easy medication in terms of standard dosing and administration (as it can be given peripherally or centrally without premedication).

In terms of duration, a standard basiliximab induction course (40 mg total) provides about 8 weeks of IL-2 receptor saturation.

The side-effect profile of basiliximab is pretty much the most benign of any medication we’ll talk about today. Hypersensitivity reactions are the only truly concerning one, and these are very rare.

Antithymocyte globulin (ATG) (rabbit, Thymoglobulin®) and (equine, ATGAM®)

As you noticed, there are two drugs in this category, and they’re delineated by animals. That’s because these drugs are produced by immunizing either a rabbit or horse with human thymocytes, then taking the resulting polyclonal antibodies and infusing them back into humans as an induction agent.

Weird, right?

These globulins cause lymphocyte depletion, but rabbit ATG has some added perks like interfering with B-cells, dendritic cells, and adhesion molecules.

Y’all may not know this, but I (Steph) never pass up an opportunity to show off beautiful horses. Tangentially related to this post? Sure, but #horsecrazy. (Image)

Rabbit ATG is the more commonly used of these two in solid organ transplant. Dosing for either of these varies by center, but in general each is a multi-day infusion and weight-based for the dosing. Equine ATG requires an intradermal skin test to make sure people don’t react to it, sort of like a PPD test for tuberculosis.

Both drugs should be given through a central line, though rabbit ATG can be given peripherally in rare cases. However, this requires modifying the preparation to be in a bigger volume (500 mL in most cases) along with heparin and hydrocortisone in the bag as well.

As you might imagine, we’re essentially giving an animal-based vaccine product to people, so we do need to be concerned about allergies to rabbits or horses. Also, serum sickness can present in people that have a history of close contact with the respective animal.

In terms of dose adjusting, rabbit ATG has pretty specific adjustments which are outlined in the package insert (for once, the package insert pulls through!) and are based on drops in WBC and platelets.

Alemtuzumab (Campath®)

Full disclosure: I’ve never personally used alemtuzumab at any of the centers I trained or practiced at. Centers that do use alemtuzumab are very familiar with it, so at the risk of saying something wrong, I’m going to stick to the basics. Alemtuzumab is a (humanized “-zu-”) monoclonal antibody targeting CD52 which is found on a lot of immune cells (B cells, T cells, macrophages, NK cells, and granulocytes) and causes cellular lysis. In the US, it carries approvals for MS and CLL and was pulled from the market after some company purchasing decisions… it’s now only available for transplant through the manufacturer if you had already been using it.

It’s typically a one time dose and you can administer it peripherally, centrally, and even subcutaneously. Infusion reactions can happen, so premedication is required with the standard trifecta of diphenhydramine, acetaminophen, and corticosteroids. The effects of alemtuzumab last a looong time. As in months to years.

Pharmacotherapy of Maintenance Immunosuppression

Unless you work at a transplant center, this next group of drugs is going to include the ones you see most often when patients come to fill prescriptions or are admitted to the hospital. While induction is important, it’s a pretty limited toolbox as you can see. We have a lot more to get into here, and the focus shifts to more practical things like ease of use, adverse effect profiles, and efficacy. Also, there’s a couple of NAPLEX nuggets in here we can mine out.

The most common combination of drugs you’ll see used for patients these days is a calcineurin-inhibitor (CNI, typically tacrolimus) and an anti-proliferative (typically mycophenolate) with or without a corticosteroid (typically prednisone).

Centers and organ types have different protocols, but there are some common themes to keep in mind.

First, immunosuppression intensity decreases with time from transplant but never completely goes away. This decrease in intensity could mean using fewer agents or lower dosing of these agents. On the other hand, though, intensity might increase based on signs or episodes of rejection.

Second, when deciding on a regimen, a lot of patient-specific factors are at play. To name a few, these would be development of adverse effects on a drug, comorbidities, malignancies, and patient preferences.

Lastly, we don’t have a great way to measure the degree of immunosuppression. We use surrogate markers (namely drug level monitoring), but it’s pretty crude. Imagine if we were trying to see how effectively your diabetes is controlled, but instead of measuring blood glucose and A1C, we checked metformin levels. Yeah, that level of crude.

So on that note, let’s jump in!

Corticosteroids, again!

These are the shadows we can’t seem to quite get rid of in transplant. Corticosteroids are some of the earliest immunosuppressive drugs we had at our disposal. They work well for sure and allowed us to make a lot of progress in the field. They’re also pretty dirty medications in terms of their adverse effects though, especially in the long-run. The most common one you’ll see in transplant is prednisone, and the goal is really to run patients on as low of a dose as they can tolerate (like 5 mg daily).

If we can get rid of it altogether that’s even better, but if patients have higher immunologic risk or experience episodes of rejection, prednisone is typically here to stay.

Corticosteroids have a massive list of adverse effects, so let’s take a look at the greatest hits:

If corticosteroids had a dating profile…. (Image)

Metabolic/Endocrine
1. Increased blood sugar, lipids, blood pressure, salt and fluid retention
2. Adrenal insufficiency
Dermatologic/whole body
1. Acne
2. Linear growth suppression (pediatrics)
3. Impaired wound healing
4. Buffalo humps
5. Moon faces
6. Weight gain, obesity
Gastrointestinal
1. Ulcers
2. Nausea
Neurologic
1. Insomnia
2. Anxiety and depression
3. Unmasking of psychosis
4. Memory impairment
Hematologic
1. Increased WBC

Calcineurin Inhibitors (CNIs)

This category includes tacrolimus and cyclosporine, two drugs which revolutionized the longevity of transplants. These drugs work similarly in their end result, but they’re a bit different in their approach. Remember that a key component of T cell activation is a phosphatase called calcineurin, whose actions ultimately lead to the promotion of cytokine production, namely IL-2. These 2 drugs make intracellular complexes by binding either FK-binding protein 12 (tacrolimus) or cyclophilin (cyclosporine), which inhibit calcineurin and prevent this downstream cytokine production. Let’s take a look at each of these briefly, then regroup.

Tacrolimus was isolated from Streptomyces tsukubaensis, a bacteria found in Japanese soil, and got its name from Tsukuba macrolide immunosuppressant. If you hang around a transplant team long enough, you’ll inevitably hear it referred to as “FK” - which is a throwback to its old study drug name “FK506.”

Were those facts fun? I hope so...if not, I apologize in advance for the rest of my fun facts.

Anyway, tacrolimus has a lot of different formulations including immediate-release capsules (Prograf®), extended-release capsules (Astagraf®) and tablets (Envarsus®), granules for suspension (Prograf® granules), compounded suspensions, and IV (Prograf®). The immediate-release capsules can also be used for sublingual administration when we don’t have enteral access.

Although it’s gotten harder with USP 800 categorizing CNIs as hazardous meds, the immediate-release capsules can also be used for sublingual administration when we don’t have enteral access. Since we bypass first-pass metabolism and Pgp (more on this in a bit), we usually dose reduce in a 2:1 PO to sublingual ratio in this circumstance. (In pediatrics, I’ve done it as 1:1 since kids aren’t all that great at keeping gross powder under their tongue.)

Why not just use IV? While this is common with stem cell transplant, most solid organ programs cringe at using IV due to higher instances of neurotoxicity and nephrotoxicity.

Food does impact the absorption of tacrolimus, and there are two schools of thought on this. Some will say tacrolimus must be taken on an empty stomach all the time, which is certainly consistent, but challenging. Others will tell patients to just be consistent with how they chose to do it - that is if you want to take the morning dose with breakfast, just always take with breakfast; if not, just always take it on an empty stomach.

Alright, on to CNI option #2.

Cyclosporine was the first CNI on the market and also comes in a variety of forms. There are two main flavors though: non-modified and modified cyclosporine. Non-modified cyclosporine (Sandimmune®) is the real OG and comes as immediate-release capsules, oral solution, and IV. Modified cyclosporine (Neoral®, Gengraf®) comes as capsules and oral solution.

Med safety and NAPLEX alert! These forms are NOT interchangeable and are a source of errors for patients on cyclosporine. The enteral absorption of non-modified cyclosporine is pretty erratic and to help stabilize this, it was “modified” to be a lipid microemulsion.

We won’t go into the nuances of all these formulations, but know that if switching between formulations, you’re going to want a transplant pharmacist involved as this gets confusing and is our forte.

Of the two, tacrolimus has become the runaway favorite, mainly due to reduced rejection severity, more reliable PK, and fewer drug interactions.

Speaking of kinetics and metabolism, there are some key commonalities and differences here:

Both drugs are substrates of Pgp and CYP3A4...meaning both have a boatload of drug interactions. It’s important for patients and providers to know that they should run new medications by the transplant team to make sure we head off toxicities or subtherapeutic levels.
Tacrolimus is also a substrate of CYP3A5. Definitely not the most popular CYP at the watercooler (get it), but this has important pharmacogenomic implications as not everyone expresses 3A5. There are functional (*1) and non-functional (*3, *6, *7) 3A5 alleles, with the *1 allele being more common in African American, Asian, and Latino populations. The presence of a *1/*1 diplotype is classified as an extensive metabolizer, a *1/*3,*6, or *7 diplotype is an intermediate metabolizer. Diplotypes without a *1 allele at all are classified as poor metabolizers. This means that extensive and intermediate metabolizers typically require higher doses of tacrolimus compared to poor metabolizers.
Cyclosporine sets itself apart though by inhibiting CYP3A4, Pgp, OATP, and BCRP, whereas tacrolimus doesn’t.

Tacrolimus and cyclosporine are narrow therapeutic index drugs, and you’re going to see patients on all sorts of doses… and that’s okay! The dosing of both of these is based on therapeutic drug monitoring with trough levels. These trough levels are most useful when drawn ~30 minutes before the dose and as close to the interval of dosing as possible (i.e., 12 hours after the last dose for a Q12H regimen). Trough level goals are typically a range that gets lower as patients get further out from transplant. It’s ultimately patient specific and depends on...you guessed it...organ type, center protocols, time from transplant, and individual patient factors. Ballparks for trough levels are 5-15 ng/mL for tacrolimus and 100-300 ng/mL for cyclosporine.

It’s not uncommon that in clinic or inpatient these trough levels get drawn after a dose was recently given, which will give you a high level and set alarm bells ringing. Don’t panic! Just remember that it’s important to always assess the timing of levels - just like vancomycin.

Other times where drug levels are unexpectedly elevated include inhibiting drug interactions and infectious diarrhea. With infectious diarrhea, both of these drugs are effluxed by Pgp in the gut, so with inflammation and damage to the GI lumen, Pgp is suddenly not as prevalent and therefore not pumping tacrolimus/cyclosporine back into the GI tract, leading to higher serum levels.

Adverse effects are overall pretty similar between the two, and when counseling patients on these, I break it up into buckets:

Nephrotoxicity
Neurotoxicity (tacrolimus > cyclosporine)
Long-term concerns
1. Diabetes (tacrolimus > cyclosporine)
2. Dyslipidemia (cyclosporine > tacrolimus)
3. Hypertension
4. Malignancies (namely skin cancers)
Electrolytes:
1. Decreased magnesium
2. Increased potassium
Individual drug concerns:
1. Tacrolimus: alopecia, QT prolongation
2. Cyclosporine: gingival hyperplasia, hirsutism

Anti-metabolites

Once again we have two drugs in this category, but they aren’t all that similar, so let’s cover them separately. These agents are typically used as add-ons to a CNI. If we get into trouble with infections (particularly viral infections), these meds also tend to be the first on the chopping block to temporarily dose reduce or even discontinue to lower the overall immunosuppression burden.

Mycophenolate

This drug inhibits inosine-5’-monophosphate dehydrogenase, which is an enzyme necessary for de novo production of guanosine nucleotides. It primarily affects lymphocytes due to their reliance on de novo purine synthesis. It comes in a couple different flavors.

Mycophenolate mofetil (CellCept®) is available as capsules, tablets, oral suspension, and IV - typically dosed as 1000-1500 mg PO BID. Mycophenolate sodium (Myfortic®) is a delayed-release enteric coated tablet only and is typically dosed at 720 mg PO BID. Conversion between these formulations is easy enough to cover in that 1000 mg of mycophenolate mofetil = 720 mg of mycophenolate sodium. Dosing is actually fairly standardized with these in that we don’t typically monitor levels, though if we do, we look at the AUC with several lab draws.

Mycophenolate undergoes glucuronidation and enterohepatic circulation, and thankfully doesn’t have many drug interactions to worry about. PPIs and antacids can reduce absorption. Bile acid sequestrants should be avoided, and sevelamer needs to be separated out by 2 hours. The more common ones that are concerning are primarily pharmacodynamic in nature for adverse effects.

When you learn about another new drug that causes nausea, vomiting, and diarrhea. (Image)

Most drugs list the triad of nausea, vomiting, and diarrhea as adverse drug effects (ADE), and we sort of nod appreciably and move on. With oral and IV mycophenolate though, this is a pretty big toxicity and can even lead to colitis. Mycophenolate sodium is anecdotally thought to be more well-tolerated in this regard, but there’s not much hard evidence out there for this.

As you can imagine, a drug that inhibits lymphocyte proliferation might lead to myelosuppression, which is indeed another key ADE for mycophenolate.

The last really important one to cover is teratogenicity, which landed mycophenolate with a REMS program. We need to take care that child-bearing age women are aware of this risk and take appropriate contraceptive precautions (outlined further on the REMS site), especially because mycophenolate teratogenicity happens early in gestation. This doesn’t mean people can’t ever become pregnant though - they just need to work with their transplant team to allow for safe titration off mycophenolate.

Azathioprine

This is one of the OG transplant drugs. Before we had all of these other tools, azathioprine and steroids really were the workhorses. It’s largely been phased out by mycophenolate these days, but it is still pulled out occasionally. Azathioprine similarly inhibits DNA and RNA synthesis, but it does so by masquerading as a purine analog.

While doing its thing, It undergoes a few conversions, and this metabolism has some pharmacogenomic considerations. Azathioprine itself is converted to 6-mercaptopurine and then thioinosine monophosphate. These metabolites are inactivated by thiopurine methyltransferase (TPMT), and a deficiency in TPMT function can lead to over immunosuppression - so patients should be checked for TPMT deficiency prior to initiation of azathioprine. (NAPLEX ALERT!)

Azathioprine is also metabolized by xanthine oxidase, and the most important drug interactions to remember are with xanthine oxidase inhibitors - allopurinol and febuxostat. Concurrent allopurinol use requires an azathioprine dose reduction to ⅓ of the current dose, and febuxostat is contraindicated for concurrent use.

Mammalian Target of Rapamycin (mTOR) Inhibitors

Once again, we have two drugs to cover: sirolimus (Rapamune®) and everolimus (Zortress®). Fun fact time again! Sirolimus is also a drug we owe to a bacteria production, and this one was isolated from samples on Easter Island. The original compound name (rapamycin) and brand name (Rapamune®) pay homage to the native name for Easter Island, Rapa Nui.

These drugs are kind of the oddballs of the transplant world. They definitely have a place in therapy with some advantages over CNIs, but they’re not perfect…and we’re still tweaking regimens with them. Sometimes they’re used as CNI replacements, and other times they’re used in combination with CNIs to allow for lower CNI levels.

mTOR inhibitors provide immunosuppression by...well...inhibiting mTOR.

Just kidding! Let’s take a closer look.

Sirolimus and everolimus bind FK-binding protein 12 - yes, like tacrolimus. But unlike tacrolimus, this complex goes on to inhibit mTOR, thereby inhibiting the activation of T and B cells that happens via IL-2 and other cytokines. Bottom line is kind of the same effect of CNIs; however, mTOR inhibitors have some added perks. The oncology peeps will recognize these as they inhibit angiogenesis and the proliferation of fibroblasts. In heart transplant, these are intriguing agents as they seem to help limit coronary allograft vasculopathy through their actions on smooth muscle and endothelial cells. Their niche is kind of in these additional benefits and also to minimize nephrotoxicity of CNIs.

Both are available as oral tablets and sirolimus also comes as an oral solution - so no IV forms here. Both undergo metabolism via the CYP3A system, and Pgp is involved in GI efflux, meaning our boatload of drug interactions is back on the table.

Just like CNIs, each of these needs therapeutic drug monitoring with trough levels again, but a key thing with these is their long half-life. Sirolimus clocks in at ~62 hours and everolimus at ~30 hours. There’s not much utility in getting levels sooner than 3-5 days after dose changes/starts, but sometimes it’s done to make sure we’re on track. Sirolimus requires a loading dose and is typically given every 24 hours (although in pediatrics, I’ve seen it done every 12 hours before due to difficulty getting levels up). Everolimus is typically given every 12 hours without a loading dose.

Trough goals can be all over the place depending on the center and how these are being used (i.e., for CNI replacement vs CNI sparing). For an idea though, ballpark ranges are 5-24 ng/mL for sirolimus and 3-8 ng/mL for everolimus.

The adverse effect profiles for mTOR inhibitors are quite large and diverse, so let’s stick to the greatest hits again:

Proteinuria and dyslipidemia (particularly increased triglycerides)
- If possible, I get a baseline urine protein and cholesterol panel before starting these meds.
Development of diabetes
Impaired wound healing
- Neither mTOR inhibitor is used immediately post-transplant (rather, they’re typically started at least 30 days out from surgery).
- In a similar vein, they’re also associated with mucositis and stomatitis (mouth sores).
Decreased blood cell counts (neutrophils, hemoglobin, platelets)
Non-infectious pneumonitis (particularly in lung transplant)
Male infertility
Lastly, these carry some boxed warnings for instances of arterial thrombosis when used as de novo immunosuppression in liver transplant (sirolimus) and kidney transplant (everolimus), which essentially cuts off blood supply to that organ and leads to graft loss. No bueno indeed.

Costimulatory blocker

No plural on this category because we only have one drug here!

Belatacept (Nulojix®) is a unique immunosuppressant in both its mechanism and delivery. (FYI, after my residency, it was drilled into me that this is pronounced bella-ta-cept, not buh-lat-a-cept. Apologies for my Northerner phonetics.)

Remember when we talked a long time ago about T-cell activation, and there was that costimulatory signal thing called signal 2? That’s what belatacept is blocking here.

Belatacept is available as an IV infusion only, and it’s well tolerated. So no premedications to worry about. Its place in therapy is really to replace CNIs in kidney transplant, and it can be done a couple different ways. If used right from the get-go post transplant, it’s a weight-based dose on the day of transplant and then on days 5, 14, and 28. After that, it’s given every 4 weeks. If we’re converting someone over from a CNI, we gradually taper the CNI dose while starting up belatacept. The schedule is different, but just know that there’s a transition period there.

Overall, belatacept is pretty well tolerated. It has some instances of peripheral edema, anemia, and GI upset. Viral infections in particular seem to pop-up in patients on belatacept, which may require re-working the immunosuppression plan.

The elephant in the room here is the boxed warning that patients have to be Epstein-Barr virus (EBV) POSITIVE to get belatacept. Seems weird, right? EBV is a bigger conversation for another time, but here’s the quick and dirty.

EBV is in the same family of viruses (herpesviridae) as varicella and herpes, and if you know anything about these, you know that infections with herpesviridae never really go away. EBV itself is the most common cause of mononucleosis, a.k.a. mono, and is problematic because it sets up shop in epithelial cells and B cells. In its dormancy period, also called latency, EBV stays busy and can spur proliferation and immortalize B cells...which sounds a lot like cancer, right?

That’s because it is.

Post-transplant lymphoproliferative disorder (PTLD) is a term for B cell proliferation due to immunosuppression after transplant. Not all PTLDs are caused by EBV, but it is a big risk factor, especially if your immune system has never seen EBV before and can’t take care of infected cells. The problem with belatacept is that in the phase 2 and 3 trials they saw an increased risk of PTLD in EBV negative transplant recipients (i.e., people that have never been exposed to EBV in the past). In particular, they saw an increased risk of CNS PTLD, which is pretty devastating. So, the bottomline is that patients need to be known EBV IgG positive prior to starting belatacept.

For those patients that qualify, belatacept sounds like a pretty good deal though, doesn’t it? No oral CNI, less nephrotoxicity, only have to go in once a month for an infusion. Depending on lifestyle, it can be a great option, but some people prefer to not visit the infusion center every month and want an oral medication.

Pharmacotherapy for Episodes of Acute Rejection after Transplant

Acute rejection is when the immune system builds a strong attack against the transplanted organ. This is also a big topic and varies amongst organ groups somewhat, so we’ll just take a 10,000 foot overview.

To talk about the treatment of rejection, we need to talk about the two main pathways for rejection as these guide treatment. Keep in mind though, that mixed rejection is also common, and these therapies can overlap in that case.

Cellular Rejection

This subtype of rejection is mediated by T cells attacking the graft, and the risk for this is highest in the early transplant period (less than 6-12 months). With this type of rejection, we need to target T cells themselves. This is typically done with corticosteroids up front and possibly lymphocyte depleting agents (antithymocyte globulin, alemtuzumab), if the rejection episode is bad enough or resistant to steroids.

Antibody-Mediated Rejection (Humoral Rejection)

In this subtype, antibodies against the transplanted organ are the primary drivers. This type of rejection is most commonly associated with non-adherence to transplant medications or pre-existing antibodies within the recipient. If you’ve read Steph’s post, you’ll remember that B cells transforming into their more mature siblings, plasma cells, are responsible for antibody building. These antibodies direct the attack against the new organ, and our primary goal is to shut this process down through antibody removal (plasmapheresis) and immune modulation (IVIG). If necessary, we can target B cells (rituximab) or plasma cells (bortezomib), and as a last resort, we may perform a splenectomy. Often used as salvage therapy, we can use eculizumab to shut down the complement-mediated processes as well.

A quick summary of common treatment pathways for acute rejection.

The tl;dr of Transplant Pharmacy

Whew, that was a heck of a lot of info! I apologize if your brain is buzzing right now! I hope this post helps bring to light some of the nuances of transplant pharmacy and also highlights that getting a transplant doesn’t mean the end of a complicated medical patient.

We do our very best to help these patients thrive with their new organ, and I’m thankful to be part of this field everyday as it touches on everything from critical care to ambulatory follow-up. I hope you enjoyed the post, and there’s a lot more to cover on this field in the future!

P.S. A final thought from Steph here… If you haven’t already, please consider registering with Donate Life to be an organ, eye, and/or tissue donor (this includes being a live donor, FYI!). You should also check out Be the Match, which is the registry for bone marrow and stem cell donation (also a live donor process!).

We’ll wrap up with this quick overview guide of the transplant medications introduced in this post. Happy learning!

The Complete (but Practical) Guide to Solid Organ Transplant