Time Stamps

  • 02:41 Pearl 1 – Types of Immunosuppression
  • 14:31 Pearl 2 – Medication Reconciliation
  • 22:36 Pearl 3 – AKI in the Transplant Patient
  • 31:53 Pearl 4 – Infections in the Transplant Patient
  • 40:00 Pearl 5 – Life with a Kidney Transplant

Show Notes

Pearl 1: Post-transplant immunosuppressive medications

  • Maintenance immunosuppression:
    • Necessary to prevent rejection of the transplanted kidney 
  • Transplant regimens:
    • Usually contain
      • Tacrolimus
      • Mycophenolate
    • Sometimes contain
      • Prednisone
    • Newer medication
      •  Belatacept
        • Can only be given to EBV IgG positive patients
  • Immunosuppressive Medications:
    • Calcineurin inhibitors: Tacrolimus and cyclosporine:
      •  Block IL-2 production in T-cells.
      • Given every 12 hours  
      • Trough level should be taken just prior to the next dose
        • Goal – avoid toxicity and maintain a therapeutic window
      • Side effects:
    • Mycophenolic acid:
      • Inhibits T and B lymphocyte proliferation by blocking purine synthesis 
      • Comes in two forms:
        • Mycophenolate mofetil (CellCept)
          • Original drug
          • Can cause GI upset
        • Enteric coated mycophenolate sodium (Myfortic)
          • Less likely to cause GI upset
      • Side effects: 
        • Bone marrow suppression and gut toxicity 
          • Can be spaced out to three times daily to reduce side effects
    • Prednisone:
      • Decreases neutrophil movement across capillaries 
      • Use according to local immunosuppressive protocols and underlying kidney disease

Pearl 2: How do you do a good medication reconciliation? What do you need to be mindful about in post-renal transplant patients’ med rec?

  • Transplant regimens can be complex!
    • Understand what medications they take and when
      • Assess for medication compliance
      • Assess for possible drug-drug interactions (not comprehensive)
        • Medications that increase levels of tacrolimus: 
          • Calcium channel blockers 
          • Antifungals
          • Macrolides
        • Medications that decrease levels of tacrolimus:
          • Anti-seizure medications
          • Ciprofloxacin
        • Medications that decrease levels of mycophenolate: 
          • Calcium carbonate 
          • Magnesium carbonate 
          • Proton-pump inhibitors
      • Note: Clinical context can also affect the levels of tacrolimus
        • Example: Diarrhea can affect tacrolimus trough levels variably in some patients! 
          • Faster GI transit → Less breakdown of tacrolimus by p-glycoprotein  → higher trough levels

Pearl 3: AKI in patients post-transplant

  • Assess acute kidney injury in the transplant patient similar to how it is assessed in patients with native kidneys!
        • Pre-renal 
        • Renal 
        • Post-renal
    • Pre-renal AKI post-transplant:
      • Decreased oral intake → hypovolemia
        • As they may be used to fluid restrictions from before the kidney transplant
    • Intrarenal AKI post-transplant:
      • Tacrolimus can be nephrotoxic. Thus, we aim for trough levels within the therapeutic window
        • In the first few months post-transplant
          • Trough levels should be 10 to 12 ng/mL
        • Approximately 6 to 12 months post transplant
          • Trough levels should be around 5 to 7 ng/mL
        • For chronic transplant patients, the target can be individualized to:
          • 4 to 6 ng/mL or 
          • 5 to 7 ng/mL or
          • 6 to 8 ng/mL
      • Acute rejection can also cause increased creatinine level (more in Pearl 5)
    • Post-renal AKI post-transplant:
      • Assess causes using kidney ultrasound  
      • Place a Foley catheter if there is significant hydronephrosis
      • Percutaneous nephrostomy may be necessary in cases of ureteral strictures

Pearl 4: Infections in patients post-transplant

  • Increased risk infections post-transplant:
    • CMV
      • Serologic status is determined for both donor and recipient prior to transplant
        • Highest risk of infection if donor is POSITIVE and recipient is NEGATIVE
      • Appears in first year post-transplant
      • Fever, diarrhea, malaise, leukopenia, and mild hepatitis
    • EBV
      • Serologic status is determined for both donor and recipient prior to transplant
        • Highest risk risk of infection if donor is POSITIVE and recipient is NEGATIVE
      • Presents as:
    • BK virus
      • Asymptomatic 
        • Screening is required to detect high viral load
        • Can cause kidney inflammation and injury
  • Measuring viral load with PCR is useful to determine whether or not a patient is presenting with active infection!

Pearl 5: Life with a Kidney Transplant

  • Acute transplant rejection:
    • Asymptomatic
      • Frequent labs post-transplant to carefully monitor creatinine for rejection
      • Requires biopsy for diagnosis of rejection
  • Increased risk of certain cancers, particularly those that are related to ones that are kept in check by the immune system:
    • Non-melanoma skin cancer
      • Annual dermatology appointments are recommended
    • Oncogenic viruses
      • EBV → lymphoma
      • HPV → anogenital and oropharyngeal cancers
      • Hepatitis B → hepatocellular carcinoma
      • Hepatitis C → hepatocellular carcinoma
    • Routine age-appropriate malignancy screening is important!

Transcript

Dr. Shreya Trivedi: This Core IM episode this month will count for CME credit with American College of Physicians. We’ll link to the URL in the show notes. Follow the link, complete the 3 questions and get CME credit. Without any further ado, let’s get into it! 

Dr. Martha Pavlakis: I think every nephron is precious. And I think the CKD native kidney patient is not different than the CKD transplant patient. We think of the transplant as this gift from another person or a family. And it is. But our own kidneys are gifts too. 

Dr. Shreya Trivedi: That’s Dr. Martha Pavlakis, a transplant nephrologist at Beth Israel Deaconess Medical Center and the chair of the Kidney Transplant Committee of the Organ Procurement and Transplantation Network. A mouth full! But, basically, she’s a big deal! Welcome to Core IM 5 Pearls Podcast, bringing you high-yield, evidence based pearls. I am Dr. Shreya Trivedi. And today I am joined by…

Dr. Marcus Foo: Hi, I’m Marcus Foo, a nephrology fellow at Beth Israel Deaconess. This is an amazing opportunity to come onto the show and discuss the best renal replacement therapy around – the transplant!

Dr. Shreya Trivedi: Ah, we did learn that in the pre-transplant episode, so I am excited to learn so much more! Let’s get into what we’ll be covering today. Test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Marcus Foo: Pearl 1 – Types of Immunosuppression

Dr. Shreya Trivedi: What are the most commonly seen side effects we see with tacrolimus and mycophenolate?

Dr. Marcus Foo: Pearl 2 – Medication Reconciliation

Dr. Shreya Trivedi: And what medications increase the amount of tacrolimus and increase toxicity?

Dr. Marcus Foo: Pearl 3 – AKI in the Transplant Patient

Dr. Shreya Trivedi: What causes of acute kidney injury are unique to renal transplant recipients?

Dr. Marcus Foo: Pearl 4 – Infections in the Transplant Patient

Dr. Shreya Trivedi: When a patient has a fever, what are the viral syndromes we should work up and when? 

Dr. Marcus Foo: Pearl 5 – Life with a Kidney Transplant

Dr. Shreya Trivedi: What are signs and symptoms of rejections and which cancers are increased in prevalence in the transplant population?

Dr. Shreya Trivedi: Okay, so often I will encounter a patient who is post kidney transplant, and their on a bunch of immunosuppressive medications that I have a vague recollection from some board exam about but I haven’t really synthesized the practical things I should know or expect about these meds.

Dr. Martha Pavlakis: So what I tend to tell patients is, I introduce the concept of immune suppression and I literally say it the same way every single time. I say, unless you have an identical twin, which so far I haven’t heard that you had, the kidney comes from somebody who is enough genetically unlike you that your body treats that tissue as if it’s an infection and your immune system, which is geared up to fight infections, will actually attack the kidney unless we give you specific medications to lower your body’s immune system. These medications are called immunosuppressants and you have to take them for the life of the transplant. It’s not like once the transplant’s working, you can stop the meds your body never forgets. 

Dr. Shreya Trivedi: The body never forgets! Oh, I cannot wait to use that next time I’m counseling patients on the importance of these immunosuppressant meds.

Dr. Martha Pavlakis: The patient usually is discharged to home on just tacrolimus and mycophenolate with, or without prednisone. And that is true for, I would say over 90% of transplants done in this country. And that’s where the fun begins.

Dr. Marcus Foo: Aha! So let the fun begin with those big three maintenance meds that prevent rejection of the transplanted kidney.

Dr. Shreya Trivedi: Yeah, and I guess because we don’t usually see the induction immunosuppression that happens right after transplant, we can just focus on maintenance medications that we see more commonly! Tacrolimus, mycophenolate and prednisone.

Dr. Marcus Foo: So let’s start with tacrolimus and its sister cyclosporine. They are part of the calcineurin inhibitors group, and tacrolimus and cyclosporine work by blocking the production of IL-2 in T-cells, and T-cells normally activate other immune cells.

Dr. Shreya Trivedi: Okay, so if there is no immune cell activation, that means there is no rejection of the new kidney, right?

Dr. Marcus Foo: Yeah, Shreya, that’s exactly the hope! And we know that things get pretty dicey when it comes to timing tacrolimus just right. 

Dr. Shreya Trivedi: Oh yes, that brings up the pain point I remember too well, which is trying to get that trough level at that right time to let us we are doing a good job of keeping that immune system in check.

Dr. Karin True: They’re dosed, ideally every 12 hours. And we get a trough level at the, sort of 11 hours and 59 minutes before the next dose. So again, in a perfect world, that’s how we would do it. And what tends to happen is a transplant patient hits the door of the ER, maybe they took their drug two hours ago. Now somebody gets a critical tacrolimus level call from the lab and says, “oh, this is critically high.”

Dr. Shreya Trivedi: That’s Dr. Karin True, a transplant nephrologist at UNC Chapel Hill describing something that happens all the time, especially on the floors, right? When the patient didn’t get their morning dose on time but they did get that tacro level with their AM labs.

Dr. Marcus Foo: And the same thing happens with cyclosporine, tacrolimus’ now less-popular sibling.  

Dr. Shreya Trivedi: Okay, so pretty much, unless you know that the trough was obtained as much as possible right before that next dose is due in 12 hours, it’s a random level and like sad to say, kind of useless!

Dr. Marcus Foo: And to add a little bit more spice here, stopping the tacrolimus because of a random trough is something you should almost NEVER do.

Dr. Shreya Trivedi: Uh it sounds like you’re saying from some painful experiences! And so I guess, trying to the trough level to make sure our patient’s immune system is under control is important, but we’re also getting that level to make sure we’re avoiding any toxicity.

Dr. Martha Pavlakis: So it’s a little bit tricky, but they, the calcineurin inhibitors like cyclosporine and tacrolimus, their biggest toxicity is neurotoxicity. So tremulousness headaches, perioral numbness, super common, especially at higher levels.

Dr. Karin True: Tacrolimus, um, can cause hypertension. Tacrolimus can cause some hair loss, which is, is particularly, our female patients don’t like that at all. The men don’t either, but mostly the female. Cyclosporin interestingly can cause hair growth. One of the other, it can cause sort of harder to control hypertension. It can cause gingival hyperplasia.

Dr. Marcus Foo: I’m going to add that tacrolimus and cyclosporine have been known to cause new onset diabetes after transplant, or NODAT.  And this is seen more commonly in tacro use than cyclosporine.

Dr. Shreya Trivedi: Is that what the cool kids are abbreviating it to now?! NODAT?

Dr. Marcus Foo: Absolutely! And you know, nephrologists are the coolest specialty and you better NO DAT!

Dr. Shreya Trivedi: Oh! HAHA, that was good, that was good. Okay, so it sounds like these calcineurin inhibitors – tacrolimus, cyclosporine – it causes neuro symptoms like headaches, tremulousness, and things that we don’t love to see in primary care – hypertension and new onset diabetes after transplant, NODAT, especially if they are on tacro. And then more specifically, tacrolimus can cause some hair loss and cyclosporine can cause some hair growth. 

Dr. Marcus Foo: That’s right, so let’s move onto the second transplant maintenance medication, mycophenolic acid. Its prodrug is mycophenolate which is what we’ll be dealing with most often.

Dr. Shreya Trivedi: Okay, and then Marcus, can you remind us, how exactly does mycophenolate work in post-transplant patients?

Dr. Marcus Foo: So mycophenolate works on stopping purine synthesis. 

Dr. Shreya Trivedi: Oof, I have not thought about purine synthesis in a while.

Dr. Marcus Foo: Me either, Shreya! You know, immune cells are making so much DNA and RNA which are made from purines, so mycophenolate sounds like a perfect drug to slow down these immune cells!

Dr. Shreya Trivedi: Yeah, and I guess when I think about medications that slow down cell division, I do start to worry about side effects.

Dr. Martha Pavlakis: The anti-metabolites like mycophenolate, mycophenolate mofetil, mycophenolic acid, azathioprine, those affect rapidly dividing cells. So bone marrow toxicity and gut toxicity. Those are, are, you know, the two most common. So leukopenia, uh, anemia, thrombocytopenia and, uh, diarrhea and stomach upset. Very common in those patients.

Dr. Shreya Trivedi: So basically with the bone marrow toxicity, the patients on mycophenolate can expectedly have pancytopenia, particularly the leukopenia, and then with gut toxicity, they’re going to maybe feel bloating, diarrhea, GI discomfort.

Dr. Karin True: Part of the way we deal with side effects from, from CellCept and Myfortic is to space out the doses. So this is not a med where you have to give it exactly 12 hours apart. So if you have somebody who’s taking, you know, 540 milligrams, twice a day of Myfortic, which is three pills twice a day, and they’re having a lot of GI side effects. Sometimes we’ll have them take two in the morning and two in the afternoon and two at night. And sometimes that helps.

Dr. Marcus Foo: So the take away here is that some patients take a big dose twice a day, you can split it into smaller doses 3 times a day or spread out the doses to offload the GI tract to make it more palatable.

Dr. Shreya Trivedi: And I guess the good news is with mycophenolate, is that you’re not chasing levels exactly 12 hours like we were with tacro or cyclosporine. And we kind of have that opportunity to space that out mycophenolate as we wish.

Dr. Marcus Foo: And the other thing we can do is keep in mind that mycophenolic acid can come in two main forms. Mycophenolate mofetil, or CellCept, which is the original drug, but can give you belly aches. And then there is an enteric coated mycophenolate sodium, also known as Myfortic, which is less likely to give you GI upset.

Dr. Shreya Trivedi: Hmm, I feel like that is an important distinction to keep in mind. How am i gonna remember this? Mycophenolate mofetil versus mycophenolate sodium? HA! Maybe, thinking about the one that ends with sodium is our friend! The one that we like, less GI upset? Maybe for the first time, the one that ends with sodium is our friend!

Dr. Marcus Foo: As a nephrologist please, don’t hate on my sodium! And I know for a fact, that sodium is my friend!

Dr. Shreya Trivedi: I appreciate that! Okay, how about we round out that maintenance trio with prednisone? I will say, though, often times, I’ll see patients post-transplant, some are just on tacrolimus and mycophenolate, and some are on tacrolimus, mycophenolate, PLUS prednisone. So, I’m curious, whats up with the discrepancy here?

Dr. Marcus Foo: So I love a little bit of drama and I noticed that UpToDate authors and Specialty guidelines, KDIGO, in this case disagree about the role of steroids. So, KDIGO says that steroids should not be involved in maintenance and UpToDate says they should. What’s up with that?

Dr. Martha Pavlakis: The KDIGO guidelines are really, it’s G is global, so they’re designed to sort of create a standard across the whole globe of transplanting centers that people can use as a basis to then develop their own protocols based on local standards of care and other guidelines. Steroid withdrawal got really popular once we had tacrolimus and mycophenolate because it was shown that those two drugs were so much better at preventing rejection than the old combination of cyclosporine and azathioprine.

Dr. Marcus Foo: So most programs have their own protocols and even within the programs, some patients get the prednisone and some don’t.

Dr. Martha Pavlakis: So if you were transplanted in ‘02, you are likely on a triple regimen. We wouldn’t change it if you’re doing well. Our steroid continuation is reserved for the following conditions. Number one, their ESRD is caused by either HIV nephropathy or IgA nephropathy. Those are conditions that are either at higher risk for rejection in terms of HIV or risk of recurrence of disease in IgA nephropathy. And then we continue steroids from the time of transplant in people who we deem to be HLA medium or high risk, which we define as antibodies against the donor or so-called DSAs, either historically or current at the time of transplant, those people stay on steroids for life.

Dr. Shreya Trivedi: So we’ll get more into what DSAs are in Pearl 2. But it sounds like a lot depends in terms of risks and benefits, and what that underlying condition the patient has in terms of starting steroids. Steroids are great for immune suppression, but as we talked about in our recent steroid episode, come with a ton of side effects! 

Dr. Marcus Foo: That’s right, Shreya. And the last thing that our reviewers thought was important to sneak into this section was a newer kid on the block, belatacept. It works by blocking T-cell activation, surprise, surprise! It’s well tolerated, and you know, it’s administered by monthly infusion, and has minimal toxicity, so you’re not chasing those levels. The only thing is, is that it can only be given in patients who are EBV IgG positive, for fear of PTLD, which we’ll talk about later.

Dr. Shreya Trivedi: Ah, yeah, that’s a great point! I guess I’ll look out for belatacept, what a great word, on future medication recs! So let me recap then, the most common maintenance medications that we see at the moment for kidney transplants – tacrolimus, mycophenolate, and prednisone. With tacrolimus, those troughs really matter, and try to get them as close as possible, right before their next dose for a true trough. Side effects include neurotoxicity, hypertension, hair loss. And with mycophenolate, it affects purine synthesis so with places that have a lot of cell turnover, like the bone marrow and gut, are affected. And there are two forms, mycophenolate mofetil and mycophenolate sodium. GI upset is common with the mofetil one. And the sodium one is our friend and causes less GI upset. 

Dr. Marcus Foo: Sodium is your friend! Lastly, prednisone may or may not be on a patient’s med list based on pros and cons of being on chronic steroids, and the particular programs criteria for using steroids. 

Dr. Shreya Trivedi: So we’ve been talking a lot about medications and we just heard at the top of Pearl 1, the importance of taking these anti-rejection medications everyday. So, I’m curious, how should we approach the med rec in a patient who’s post-kidney transplant?

Dr. Martha Pavlakis: I would say the most important thing when somebody gets seen either in the outpatient clinic or admitted to the hospital is a really good medication reconciliation. And I mean, really good. Not handing them the list and saying, “here’s your med list.” That’s not adequate. I really mean naming the drugs, seeing if the person recognizes the drug, knows what it’s for, knows how many milligrams they’ve taken and whether or not they’re actually taking it as prescribed. Uh, we do that in clinic with our patients, every single time. Many of our patients use pill boxes and are on top of their refill schedule and really are quite good. But I think medication adherence and making sure that all the different EMRs and all the different providers are all in agreement, not on what the patient’s supposed to be on, but what they’re actually taking is critical. And that prevents a lot of medication errors, which, uh, can be, you know, kidney and or life threatening in some situations.

Dr. Marcus Foo: Just for the people in the back, the med rec is worth triple checking in a transplant patient.

Dr. Shreya Trivedi: Yeah, sometimes I like to ask, you know, when I’m going over the med history, “hey, how many times a week do you miss your medications?” And kind of normalize, hey, I’m not as great at taking my medications, and maybe more things will come out of that conversation.

Dr. Marcus Foo: Yeah because if we can open that up and establish some rapport, we can understand how much a patient is at risk for rejection if they’re not taking their meds on time, or missing doses. 

Dr. Shreya Trivedi: So I’m curious how bad it is if a patient doesn’t take their immunosuppression on time? Is it okay to miss a dose here and there? What exactly happens if someone doesn’t take their tacrolimus on time every once in a while?

Dr. Martha Pavlakis: Let’s say I have no anti HLA antibodies. I get a transplant from somebody with different HLA profile than me, which is gonna happen unless it’s, you know, an identical twin or a perfect match sibling. Maybe I miss my immune suppression. I don’t take it regularly. My body starts to form antibodies against the donor’s HLA, which are expressed in the kidney. Those are called DSAs. And one of the scariest things we see is the development of a de novo DSA. And that’s often delineated as d, n, small dn, capital DSA. So a dnDSA, de novo means that this person is being under immunosuppressed and they are starting to form antibodies in the blood, which are identifiable. That could cause an antibody mediated rejection. And what I tell patients is that these de novo DSAs are like armed drones and they’re circulating and they are threatening the kidney. They may not be attacking quite yet, but they’re always a threat.

Dr. Shreya Trivedi: So DSAs stand for donor specific antibodies and wow, that image de novo DSAs being armed drones circulating around, hoping to take down the precious donor kidney, is powerful and I guess just reinforces that this is nothing to play around with!

Dr. Martha Pavlakis: So we track people with de novo DSAs very carefully. We do a management biopsy. We sometimes increase their immunosuppression, trying very hard to prevent, um, a, a rejection from happening.

Dr. Marcus Foo: I do try to reinforce the importance of taking medications and immunosuppression on time every day with patients. No exceptions. But oddly enough, in my experience, when I’ve seen transplant patients get upset, it’s when their meds are late and when they’re worried about that next dose not coming on time.

Dr. Shreya Trivedi: Yeah! Transplant patients are so on top of it! And sometimes its us ordering the meds BID instead q12, or the meds taking a while to come up from pharmacy. Maybe this a good segway into thinking about another part of the med rec that comes up often which is drug-drug interactions.

Dr. Martha Pavlakis: The drug-drug interactions that affect transplant patients are so common. It’s why we, as the transplant nephrology team consult on every transplant patient where the working kidney or pancreas transplant in the hospital, whether or not they’re admitted for a kidney indication, um, I have heard people say, oh, we didn’t consult you because it’s a stroke. It has nothing to do with your kidney. And I say, everything has to do with the kidney. And it’s really not so much the kidney, it’s the med interactions. 

Dr. Shreya Trivedi: You know that’s helpful because sometimes I don’t have a specific question for transplant nephrology and I’m not sure if I should involve them, should I not? I don’t want to bother them. I have nothing to really ask them. But its good to know how much ownership that they take over their patients and seems at the very least, along with our pharmacist colleagues, can keep a pretty eagle eyes on those drug interactions!

Dr. Martha Pavlakis: So you get somebody on tacrolimus and you very well meaningly start them on diltiazem, their tarco levels are gonna shoot up. Um, erythromycin, clarithromycin, uh, Z-pack. All of these very commonly used medications will shoot up the tarco levels, fluconazole.

Dr. Marcus Foo: To recap, meds that will raise the tacrolimus levels are Calcium channel blockers like diltiazem, antifungals, and macrolides. And then on the flip side, meds that will make the tacrolimus levels go down are anti-seizure medications and anti-biotics, like ciprofloxacin. While we’re at it, antacids like calcium and magnesium carbonate, and aluminum hydroxide can bind to mycophenolate and reduce its conversion to the active mycophenolic acid. 

Dr. Shreya Trivedi: Hmm, so PPIs can raise that gastric pH enough to prevent mycophenolate’s conversion to it’s active form and and limit that absorption. 

Dr. Marcus Foo: So the recommendation from our pharmacy colleagues is to space out those PPIs from when you take your mycophenolate.

Dr. Shreya Trivedi: Ah, that’s a good trick to know and I’m glad we’re covering this because on a busy day, I don’t know if its okay to admit this, it’s very easy to skip through those pop-up alerts. 

Dr. Karin True: If you’re giving one dose of fluconazole for like a vaginal yeast infection, it’s fine. It’s not, it’ll, it might pop up a warning like on Epic or whatever, but if you’re giving one dose, it’s not gonna appreciably change those levels. So I would not be concerned about that. But if you were gonna put somebody on a prolonged course of an antifungal medicine, um, certainly we would wanna know. It doesn’t mean that they can’t have those medicines. It just means that we need to probably adjust the doses of their maintenance immunosuppression.

Dr. Marcus Foo: Yes, and another thing to keep in mind is that the clinical context is important too. Things like diarrhea can mess up how tacrolimus gets absorbed and metabolized.

Dr. Martha Pavlakis: So diarrhea is just one example. And it’s a really good one because it is also idiosyncratic. You may have one person putting out two liters of liquid stool a day and their tacro levels stay exactly the same. And another person with less diarrhea becomes terrifically tacro toxic. And then another person who was tacro toxic with diarrhea, the diarrhea resolves the tacro goes right back to normal. And another person where takes three weeks after resolution of diarrhea for the tacro levels to go back. And this inability of ours to predict who your patient is or what paradigm they’re gonna fall into is why we check levels so frequently. 

Dr. Shreya Trivedi: Oh my gosh! What a toss up, with how things like diarrhea can really impact those tacro levels. And I think, makes me really appreciate why the nephrologist or the transplant team really wants that tacro level. And the importance of getting it right and checking it right before the next dose, so we can interpret it correctly! 

Dr. Marcus Foo: So to summarize, each missed dose of immunosuppression leads to formation of new donor specific antibodies, those armed drones, which are BAD for the life of the kidney. Some medications to keep an eye out for that can raise tacrolimus in the serum are calcium channel blockers, antifungals, and macrolides. Some meds that decrease tacrolimus are antiseizure meds and ciprofloxacin. And always, always, always talk to your transplant team when transplant patients are admitted. Pretty please!

Dr. Shreya Trivedi: Okay, now we that covered medications that these patients are on, and I feel like I have a good grasp on that, let’s move to common conditions that we often encounter in the clinic or in the hospital. Starting with, when we order labs for these patients and we get back a creatinine and we see that our patient has an acute kidney injury.  

Dr. Marcus Foo: Well, Shreya, at this point in my career, I know that AKI, or acute kidney injury, is a fact of life. But I feel like the stakes are higher when it happens in a renal transplant patient. Don’t you?

Dr. Shreya Trivedi: Oh, I very much feel that! I worry that I may be doing something to actively hurt that precious, donated kidney. And kind of pains me to see that creatinine of 3, or in SI units 265 micromoles per liter, in a patient with a transplanted kidney. So I’m wondering when we do see that AKI in these patients, how should we approach it, should I be changing something? 

Dr. Martha Pavlakis: The acute kidney injury in the transplant patient really is bread and butter nephrology with a few caveats. So I start with pre-renal, intrarenal, post renal, just like you would with any person with two kidneys.

Dr. Shreya Trivedi: Okay, phew! That’s a relief. But she did say a few caveats, so I’m curious what are the different caveats or things to keep in mind for AKI in a transplanted kidney?

Dr. Karin True: So one of the hardest switches to flip that I’ve seen for patients after transplant is patients who’ve been on dialysis for 5, 6, 7, 10 years. They’re, for all of those years, they’ve been told, you know, drink, don’t drink more than a liter or two in your intervening days between your dialysis days. So practically nothing, you know. They are, it’s just driven into their heads. Like don’t drink too much, don’t drink too much. Don’t get volume overload, don’t drink too much. And then they get transplanted where like, you gotta drink, you gotta drink. There are people who really struggle with that is, is really kind of going from drinking a liter every couple of days to drinking a couple three liters every day.

Dr. Shreya Trivedi: Ah! I’ve never really thought about that. There’s basically a whole frame shift right after a patient gets transplanted. And so in that pre-renal category, asking if they’re drinking enough, is even more pressing.

Dr. Marcus Foo: So that’s the pre-renal side of things, and on the post-renal side of things, we should be thinking of obstruction. And getting an ultrasound of the transplanted kidney that usually sits in the right side of the pelvis, by the way, will give you a sense of whether or not they have obstruction.

Dr. Shreya Trivedi: Yeah, and usually when I’m looking at those ultrasound reports, there’s something about hydronephrosis. So, I’m curious, how do we triage the hydronephrosis in a transplanted kidney?

Dr. Martha Pavlakis: A lot of renal transplants actually have a little bit of hydro and a little bit of hydro is never gonna give you an AKI. So I hear mild hydro and I go, eh, I hear moderate hydro. And I immediately open up the image and look at it. Because really it’s such a subjective thing, mild, moderate, severe. Um, and I, you know, over the decades of doing this, I can look at a hydro and go, I call that moderate, ah, that’s not moderate, get a Foley in that guy immediately. When you have hydro, I just think about the entire urinary system from the urethra right up to the renal pelvis. And where do we think the obstruction is? If you have a huge bladder and moderate hydro person needs a Foley, if the bladder is decompressed and the hydro doesn’t go away, the person needs a percutaneous nephrostomy.

Dr. Shreya Trivedi: And if that creatinine, after some time, is still high, what we learned from Dr. Pavlakis is that we should actually be reaching out to our interventional radiology colleagues, not our urology colleagues since they can’t do a retrograde cystoscopy in the transplanted kidney. 

Dr. Martha Pavlakis: And often we as transplant nephrologists, we go down and talk to them and say, basically, this guy was lingering around 2 to 2.4, he’s now 3.6. Um, he’s got moderate hydro, foleys been in to date, the creatinine hasn’t changed. Can you please do a perc neph?  They understand to do the perc neph to decompress the renal pelvis, and then they can go back and squirt in a little dye and actually delineate exactly where the obstruction is. Um, usually it’s somewhere along the ureter because the ureter, if you look at the blood supply to the native ureter, it’s actually extraordinarily complex all the way down the path. So the ureteric blood supply is a bit of a delicate thing. And despite the surgeon’s best efforts, sometimes, uh, ureteric stricture happen. And they can lead the hydro with a decompress bladder.

Dr. Marcus Foo: “Strictures happen!” That might have to be my new catchphrase! But in all seriousness, the surgery for the transplants is a heroic feat. Especially in the post-op period, you might encounter issues around urine leaks, urinomas, hematomas, and vascular issues, too. More reason to get that ultrasound with doppler.

Dr. Shreya Trivedi: Yeah, right, of course! So if I was to summarize so far, some salient points in the pre-renal bucket, we gonna have to ask our patients if they are drinking enough and in the post-renal bucket, we are really going to have to pay to that imaging. So I’m curious, any quick differences in the intra-renal causes ?

Dr. Marcus Foo: Yeah, Shreya! Unfortunately there’s a few things I didn’t mention in particular about tacrolimus. That medication, that’s keeping that kidney viable, can be nephrotoxic.

Dr. Shreya Trivedi: Ah! What a double-edged sword there! Huh?

Dr. Martha Pavlakis: There is a spectrum. The tacrolimus causes an intense intravascular intra-kidney vasoconstriction and combined with hypotension from volume depletion, you can then result in an ischemic injury to the kidney. So it’s like any pre-renal, if it’s bad enough and goes on long enough, then it’s no longer purely pre-renal turns into an ischemic injury to the kidney, which is intra-renal. 

Dr. Marcus Foo: Yeah, which goes back into what we were talking about in Pearls 1 and 2. Getting that tacrolimus trough at the right time helps us avoid nephrotoxicity.

Dr. Shreya Trivedi: Yeah! Ugh, those levels rear their heads again! But I can imagine, it’s going to be hard to decipher if that AKI is really being caused by tacrolimus levels or not.

Dr. Martha Pavlakis: I actually have a patient in mind who came in with pretty bad norovirus and a lot of diarrhea and an AKI. His creatinine was normally 1.5, it was 2.2, he was a little hypotensive, his mouth was dry, he’d been pouring out diarrhea and we volume repleted him quite nicely. And the next day we sent a tacro level and while we’re waiting for it to come back, the creatinine is even a little bit higher. And we say, gee, if it was pure pre-renal, he got hydrated from the minute he hit the door, his bicarb is normalizing, his blood pressure is great, he feels better. Why isn’t the creatinine better? And then that afternoon the tacro level comes back and instead of being five to seven, it’s 18.

Dr. Marcus Foo: That is NOT GOOD!

Dr. Shreya Trivedi: Uh! And not that we need to memorize any numbers but I think it’d be helpful to get some target ranges of tacro levels we are shooting for post-transplant.

Dr. Martha Pavlakis: Early post-transplant we target 10 to 12. Over the first 6 to 12 months we get down to a target of 5 to 7. And for chronic transplant patients, their levels are either, their target levels are either 4 to 6, 5 to 7, or 6 to 8. And that slight variation is actually important. Number one because the 4 to 6 is somebody who you’re really on the downswing of immunosuppression. 6 to 8 is somebody maybe who just had a rejection episode and you want to keep them a little higher immunosuppressed. And the reason we have such a tight range is if your target is 6 to 8 and you’re 8.2, I’m going to leave you alone. But if your target is 4 to 6 and you’re 8.2, I’m going to cut your dose maybe almost in half.

Dr. Marcus Foo: The thing to keep in mind though is that this is going to be center-specific. Whether or not an institution uses steroids will lead them to have lower target troughs. And I do think there’s a lot art involved here, where the target level depends on the center, the patient, and the patient’s individualized risk.

Dr. Shreya Trivedi: Yeah, good to know. And I know we will talk about rejection more in Pearl 5, but where does rejection fit into all of this?

Dr. Marcus Foo: Yeah, I’d call that intra-renal as well. Rejection is a diagnosis of exclusion, of course, so if you’ve done the appropriate workup as above and you’re at a loss, get that biopsy to diagnose acute rejection. 

Dr. Shreya Trivedi: Awesome, yeah! So I’ve really appreciated this quick pearl on AKI in the transplanted kidney and fact that we should think about in the same way we think about it in the normal kidney! But paying attention to how they’re at higher risk for strictures, dehydration from older habits of not drinking as much, and then of course, in the intra-renal bucket, we have the diagnosis of exclusion with tacro toxicity and acute rejection.

Dr. Shreya Trivedi: Okay, now that we got AKI covered, the other thing we often see in patients with kidney transplant, especially in the hospital or even in the clinic sometimes, is they’re coming in with a fever. And feel pretty comfortable saying that the general reaction is to freak out a little bit inside.

Dr. Marcus Foo: Shreya, I know exactly what you’re taking about! And I know before my transplant rotation, I used to check the whole alphabet soup of EBV, CMV, BK, and every other combination of letters I could think of.

Dr. Martha Pavlakis: Can you explain to me why this person had CMV, EBV, and BK sent? And usually the answer is, well, you know, they’re a transplant patient. I say, you know, that’s not good enough.

Dr. Shreya Trivedi: Oh, I think we are all guilty of this. Okay, why don’t we focus then on the viral serologies for a fever workup, and how can we be more thoughtful of which viral serologies to send off and which ones we can pump the brakes on? 

Dr. Martha Pavlakis: Often we’ll say, “ooh, this could be CMV!” Send the CMV PCR. And what shows up in the computer, CMV serologies. And CMV serologies are never the way to diagnose CMV and the immunosuppressed patient. It’s the PCR. In fact, the serologies are already in the computer and most of our patients are IgG positive, um, right, because they’re adults. And if you look at their early post transplant notes, you can see what their CMV risk profile is.

Dr. Marcus Foo: So here, IgG means that their immune system has encountered the virus before. And by risk profile, we’re trying to identify if a kidney recipient is particularly at risk of becoming symptomatic from CMV or EBV from the donor’s kidney. 

Dr. Shreya Trivedi: Okay, so I can imagine the highest risk situation would be a if the donor kidney is positive for CMV and the recipient is seronegative for CMV. AKA the donor is infected with CMV and the recipient has never seen CMV and never been infected.

Dr. Marcus Foo:Yeah, that’s exactly right. And the risk of disease is usually clearly laid out in the one of post-transplant notes. You might see something like “D+/R-,” a shorthand for their sero-status, in this case D+ means donor positive and R- means recipient was negative.

Dr. Shreya Trivedi: Nice! Thank you for helping me read those hieroglyphics. I’m assuming the lowest risk profile is going to be seronegative for the donor kidney and seronegative for the recipient too?

Dr. Marcus Foo: Yeah! Good intuition! And every other combination is what I would call moderate risk.

Dr. Shreya Trivedi: Great, great! Okay, so the serologies are gonna be in the transplant notes and it’s gonna give us an idea of their risk of developing CMV, but it’s going to be the viral load that’s really going to tell us if they’re acutely viremic. 

Dr. Marcus Foo: That’s especially true when the tests are several hundred dollars a pop. It’s worth making sure that you’re checking the PCR and not repeating a serology that they already have.

Dr. Shreya Trivedi: Yeah, high value care, indeed! Okay, so now that we understand the labs a bit more, if we back up and we think about the fever presentation, which fever presentations should we send the CMV PCR in? 

Dr. Martha Pavlakis: CMV is a very specific syndrome. And it usually shows up with fever, diarrhea, malaise, leukopenia, and a mild hepatitis. And usually CMV shows up in the first year or so post transplant. So any one of those in somebody in the first year or so post transplant, it’s worth getting a CMV viral load. Um, somebody who comes in with heavy pyuria and rigors, you just wasting money getting a CMV PCR.

Dr. Shreya Trivedi: Great, thats helpful! So CMV is a typical viral syndrome with some diarrhea, leukopenia, liver enzyme abnormalities.

Dr. Marcus Foo: Yeah, that’s exactly right, Shreya. So now let’s switch to EBV. We are usually sending EBV in the patient with the classic mononucleosis symptoms of fatigue, swollen glands, and pharyngitis. But EBV does cause havoc and can increase the risk of lymphoma, too.

Dr. Martha Pavlakis: EBV PCR should be sent in somebody in whom you suspect either a post transplant lymphoproliferative disorder or a mononucleosis-like syndrome.

Dr. Shreya Trivedi: So post-transplant lymphoproliferative disorder or PTLD is a really specific condition. 

Dr. Marcus Foo: So what happens here is, when the patient’s T-cells are low from immunosuppression, EBV can come in and really amp up those B-cells causing them to multiply out of control, as the name post-transplant lymphoproliferative disorder suggests. 

Dr. Shreya Trivedi: Ah, Marcus, that sounds like a mouth full! I am going to stick with PTLD. So PTLD can can look like, of course, a fever, but also some malaise, weight loss, and a new mass or can even lymphoma in some cases. 

Dr. Marcus Foo: Yeah, it can be a real mess! But let’s move on to our third virus, BK virus.

Dr. Shreya Trivedi: Oh, all I really remember about BK is that mnemonic that BK stands for “bad kidney,” and it can cause renal failure and hematuria. I’m curious if that is accurate or what is actually looks like?

Dr. Martha Pavlakis: BK does not cause fever. And only if it’s gone undetected for a while, does it cause a, a kidney injury. BK is a screening test in an asymptomatic person. We try to pick it up well, before it causes, um, uh, kidney inflammation and kidney injury. It does not cause fever or systemic symptoms. And if the person’s within the first few years post transplant, we’re checking BK every one to three months, anyways. BK almost never suddenly wells up and causes renal failure and almost never causes fever. So to lump BK with CMV, is to be ignorant as to what those viruses do.

Dr. Marcus Foo: It’s really exciting to see Dr. Pavlakis get riled up about these viruses because she’s one of the most understanding, compassionate docs around. And I can imagine being in her shoes and watching these labs getting sent off left and right without stopping to think about the clinical syndrome. There’s a lesson learned for me for sure.

Dr. Shreya Trivedi: Yeah, totally, I can only imagine! So it sounds like BK doesn’t really present with ANY symptoms and is just brewing in the background and then could cause renal failure or hemorrhagic cystitis. And we should at least be rest assured BK is already being sent by the transplant nephrologist. 

Dr. Marcus Foo: Shreya, if you could just bear with me for a thought experiment. Let’s say we have a patient with fever and flank pain, and we ruled out pyelonephritis in the native and the donor kidney, and have negative cultures and all of that. And we have no idea whats going on. What do we do then?

 Dr. Martha Pavlakis: Then, you know, you could add on just to dot your i’s and cross the t’s, but it almost never makes sense for somebody coming in with their first presentation of fever to get EBV. Like the EBV, where you’re at your wits end, and you say, you know, let’s dot all our i’s and cross our t’s. Sure. Get a CMV PCR. 

Dr. Marcus Foo: It really sounds like the key is judicious ordering. 

Dr. Martha Pavlakis: I’m not saying never send a CMV PCR, but I can’t tell you how many times people have shown up with something that looks nothing like CMV, EBV. And certainly nothing like BK. And yet those tests are sent off. The PCR is, last I looked, which was a long time ago, but like $300 each. It’s just a waste. It’s just a waste.

Dr. Shreya Trivedi: Okay, well said! So takeaways here are check the CMV PCR, not the serology when patients has fever, diarrhea, malaise, leukopenia, mild hepatitis, especially if it’s the first year of that transplant since that’s when they’re more immunocompromised. 

Dr. Marcus Foo: And I would check EBV PCR when they have infectious mononucleosis type symptoms. That fever, swollen glands, pharyngitis. Or concern for lymphoproliferative disorders, especially if they have leukopenia or lymphadenopathy. 

Dr. Shreya Trivedi: And then last, but not least, pretty much we don’t have to send a BK viral load unless we know that they had BK virus before!

Dr. Marcus Foo: To close out the episode, let’s put ourselves in the patient’s shoes post-transplant and what their experience must be like. The two big things that come to mind are their risk of cancer and possible rejection.

Dr. Shreya Trivedi: That last one, rejection, has been on my mind this entire episode. And what does rejection really present with? Will the patient have a fever? Will they feel sick?

Dr. Martha Pavlakis: So the patients always wanna know what are the signs and symptoms of rejection. And my answer is “your labs.” If you get to the point that you’re having signs and symptoms of rejection, your kidney is hurting. You’re peeing blood, you’re uremic. It is almost too late to do anything about it.

Dr. Marcus Foo: Oof. So when rejection starts to happen, there are no signs or symptoms. Labs are drawn every few months to trend that creatinine and early on, they’re drawn weekly.

Dr. Shreya Trivedi: Wow, so what happens if we do see that creatine bumping and we start to get worried about rejection?

Dr. Karin True Day: The only way really to definitely as it stands right now, diagnose rejection is with the kidney biopsy. Um, so we can certainly be suspicious of our rejection in, in patients that have, you know, creatinine that’s rising, who may be reported being off their medicines or have something else going on. Um, but really the only way to know is to do a kidney biopsy.

Dr. Shreya Trivedi: Okay, so thinking about our patients’ experience post-transplant, yes, they are going to get frequent labs and really stay on top of their meds as much as possible to prevent rejection. What about the risk of cancer post-transplant?  What should we know about cancer in these patients?

Dr. Marcus Foo: Yeah, and just like we talked about in the kidney transplant preparation episode, a big part of keeping up with your health post-transplant is also getting cancer screening. 

Dr. Martha Pavlakis: We start the script at the very first evaluation visit because it’s important for patients to understand when going into transplant, both the risks and the benefits. Overall, on average people live longer and better with a transplant compared to staying on dialysis despite the increased risk of cancer and infection with the immunosuppression. So that’s number one. The other thing is that it’s immunosuppression related cancers, so it’s not cancers across the board that go up. Now these immunosuppressants do a really good job the immune suppression does a really good job at protecting your kidney kidney from being attacked by the immune system. But it also decreases the immune system’s other important functions, which is fighting infections in certain kinds of cancers. So the kinds of cancers which really start to go up in transplant patients, above and beyond just the normal risk of cancer in everybody. Those are cancers like skin cancers and a rare cancer of the lymph node system called lymphoma. Those two go up a lot. And cancers related to infections like papillomavirus or herpes viruses. 

Dr. Marcus Foo: So as we give immunosuppression, the worry is that some early cancers avoid detection by our patients’ native immune system.

Dr. Shreya Trivedi: Yeah and I think one thing that I didn’t really appreciate with the cancer screening, was the importance of  having annual dermatology visits and really getting that total body skin exam.

Dr. Martha Pavlakis: So we encourage you, because skin cancer is so common after transplant, even from now, even before you have a transplant, stop burning, stop tanning, you can go out in the sun as long as you’re protected. And if you find you’ve got a tan line, you haven’t put on enough sunblock, you need to put more on. So we really start the education process no matter what the person’s skin color is. And that’s very important. And the general population, it’s more often basal than squamous, but unfortunately in the transplant population it’s more squamous than basal. And so that education starts right away. And I try to reassure people because they’ll say, oh, my uncle died of colon cancer. That was awful. And I say, actually the big cancers like colon, lung, breast, and prostate, those aren’t dramatically increased in transplant. They’re tiny bit increased, but those don’t tend to be cancers controlled by the immune system. It’s cancers controlled by the immune system, oddly, skin cancers, lymphomas, and then virally mediated cancers like HCC in somebody with chronic hepatitis B or C that we are particularly concerned about. So that’s the baseline of the education we give patients. And we don’t transplant anybody who hasn’t done their baseline cancer screening yet.

Dr. Shreya Trivedi: Wow, so interesting. Now that she says, it makes sense that cancers that are kept in check by the immune system are the ones that we really need to on the look out for. My big take away in the patients experience post-transplant is to do my part in asking them, “hey, when was the last time you had labs done?” Really do a good med adherence like we talked about in Pearl 2 to avoid rejection. And checking in about their cancer screening

Dr. Marcus Foo: And that’s a wrap for today’s episode.  

Dr. Shreya Trivedi: Yeah! If you found this episode helpful, please share with your team and colleagues. Give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! 

Dr. Marcus Foo: Thank you to our peer reviewers, Drs. Sandy Nissaisorakarn, Jean Francis, Aditya Pawar. 

Dr. Shreya Trivedi: And thank you to Dr. Rahul Maheshwari for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Thank you! Take care!

References

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