#210 Kidney Transplant for the Internist

April 27, 2020 | By Cyrus Askin

A NephMadness crossover episode with @Kidney_Boy & the Freely Filtered Crew

Get inside the black box of transplant medicine as we discuss: Kidney transplant for the internist. Join Dr. Cyrus Askin, @askins_razor, one of our Curbsiders Correspondents, as he teams up with the fine folks from freely Filtered in this NephMadness episode exploring topics in kidney transplant! On this show, the gang turns to Dr. Samira Farouk, @ssfarouk, a Mount Sinai transplant nephrologist, to take the reins during this guided tour of concepts in transplant medicine that internists should be familiar with. During this episode, you’ll learn about indications for kidney transplant, immunosuppressive agents, what to watch out for in your post-transplant patients and so much more! And of course, we will talk a little NephMadness as we wrap things up. So maybe you need to learn about kidney transplant or perhaps you’re still mourning the loss of March Madness 2020 – either way, we encourage you to take a listen and hope you’ll enjoy!

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Credits

Written and Produced by: Cyrus Askin MD, Matthew Watto MD and the Freely Filtered Crew

Infographic: Cyrus Askin MD

Cover Art: Kate Grant MBChB DipGUMed

Hosts: Cyrus Askin MD, Joel Topf MD, Samira Farouk MD, Swapnil Hiremath MD, Jennie Lin MD & Matt Sparks MD

Editor: Matthew Watto MD (written materials); Clair Morgan of nodderly.com

Sponsor

We are excited to announce that the Curbsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out curbsiders.vcuhealth.org for more information.

Time Stamps

• 00:00 Announcement, Intro to Freely Filtered and NephMadness
• 04:00 Case of advanced CKD; Who/when to refer for transplant
• 12:05 Benefits of renal transplant
• 16:22 Counseling patients with advanced CKD about transplant and a bit on living donors
• 20:40 Medications after transplant; Drug-drug interactions
• 25:50 Dr. Sparks’ 30 second exam for the transplant patient; Diarrheal illness
• 32:07 Calcineurin inhibitor levels
• 36:42 Prophylaxis for long term complications
• 40:21 Allograft rejection; Bannf criteria
• 50:40 Cardiovascular risk; Statins
• 56:11 Malignancy after kidney transplant
• 60:00 NephMadness Transplant Region: Biomarkers vs Biopsy
• 72:23 Outro

Kidney Transplant Pearls

1. Early referral is key: a patient with a GFR of 20 or less makes them eligible for a transplant eval and the moment this begins, the moment they start “accruing time” towards progressing up the transplant list.
   
2. The benefits of transplant are significant, but do not manifest immediately: patients have tremendous improvement in quality of life, however, they must initially overcome potential operative/post-operative complications and avoid acute rejection, then become accustomed to any potential anti-rejection drug side-effects.
   
3. Calcineurin inhibitors (ex: tacrolimus), anti-metabolites (ex: mycophenolate or MMF) and corticosteroids (prednisone) are the drugs used in concert to try to prevent rejection. Side effects of these agents include hair growth/loss, tremor, thrush and diarrhea which should be evaluated for at every visit.
   
4. Diarrhea, in particular, should be on your radar as it could indicate any number of issues in the kidney transplant patient such as opportunistic infection or MMF-associated colitis.
   
5. TMP-SMX is almost universally used in the first year post-transplant for PCP prophylaxis, and may be used longer  for patients that tolerate it. Remember, it is also prophylaxis against Nocardia!
   
6. Transplant rejection – both acute and chronic -are complex immunological processes with different histopathologic findings on biopsy.   Hematuria, proteinuria and rising creatinine can be seen in both cases and should prompt strong consideration for biopsy.
   
7. Major complications seen in post-transplant patients include progression of cardiovascular disease and malignancies such as skin cancer, colon cancer and post-transplant lymphoproliferative disorder.
   

Kidney Transplant Show Notes 

Background and Patient Counseling

Preemptive renal transplants are most successful. A single eGFR value under 20 qualifies a patient for transplant evaluation. Dr. Topf notes that patients often still have years before they will require transplant at this point (eGFR near 20), which helps them move up the list as they spend more time on it.

Patients begin to accrue time on the transplant list the minute they start dialysis. Dr Farouk notes that 15% of patients currently receiving dialysis are listed for transplant (against an estimated 40-50% who WOULD BE eligible).

Full renal transplant evaluation takes at least 6 months even if everything goes perfectly (ex: no intervenable coronary artery disease is discovered, requiring stenting and DAPT).

Dr Topf and Dr Farouk note that the waitlists in Michigan and New York are 3-5 years and 8-10 years, respectively. In Ottawa, it may be as short as a couple of years per Dr. Hiremath. 

Improved mortality from kidney transplant lags behind surgery by at least 1 year. The quality of life improvements are tremendous and cannot be overstated!

Prepare patients for their medication (pill burden) doubling or tripling post transplant for at least the first 6 months. Dr Farouk recommends that patients bring a family member or friend to the initial visit.

Most patients have not identified living donor candidates and have not asked. Dr. Topf notes that donors DO NOT have to be family members. If patients have found a living donor then patients can be moved up the list even if their donor is not compatible. This is done through multi-patient “trades” (National Kidney Registry Swap / Exchange Program).

Patient age is a factor but not as important as comorbidities – Dr. Hiremath recalls an 80 year-old that was transplanted during his career with a good outcome. He also recommends an approach to transplant evaluation where the question is reframed from “Why should this patient get a transplant?” instead of “Why shouldn’t they?”.

Medications after Kidney Transplant 

Main medications used in these patients are immunosuppressants, most patients are on 2-3 transplant medications. These generally include a calcineurin inhibitor, anti-metabolite and corticosteroid and are generally lifelong medications.

Kashlak Pearl: Check-in with the transplant team before starting any new meds to avoid drug-drug interactions.

Calcineurin inhibitors

Calcineurin inhibitors are the backbone for post-transplant  immunosuppression -either tacrolimus or cyclosporine- with the former being 1st choice at most centers. Metabolized by cytochrome P450 enzymes (particularly CYP3A4) and thus levels must be monitored when starting inducers of P450 (e.g. carbamazepine, phenytoin, rifampin, St. John’s Wort) due to risk for subtherapeutic levels and rejection. Conversely, inhibitors of P450 (e.g. diltiazem, verapamil, macrolides, ritonavir, grapefruit juice) —-Voora AJKD 2019. *CBD (cannabidiol) is a potent inhibitor of P450 and can increase calcineurin inhibitor levels, but unpredictably since preparations do not contain standardized drug levels.

**Correction from the show: The podcast crew mistakenly labeled grapefruit juice as an “inducer”, but it is actually a strong inhibitor. Additionally, St John’s Wort is an inducer, Not an inhibitor. **

Tacrolimus trough levels (30 min prior to dose) are typically targeted at 5-7 (lower if malignancy and higher if patient has issues with rejection) —Voora AJKD 2019. Chronic Cyclosporine trough levels are typically targeting a range of 100-150. Dr Hiremath points out that these are surrogates for a patient’s degree of immunosuppression (pharmacokinetic vs. pharmacodynamic testing). Pharmacodynamic testing, for example, administering a blood pressure medication and checking the blood pressure, is ideal but unfortunately not feasible in this setting. Dr Farouk checks labs on patients every 1-2 months to assess adherence and drug levels.

Anti-metabolites

These agents interfere with DNA replication within the immune cells. Azathioprine was historically used, but mycophenolate mofetil (MMF)  is now the most common agent.

Corticosteroids

Prednisone is normally used at higher doses in the peri-transplant period and at 5 mg once daily long term.

Monitoring for Side Effects

Dr. Sparks’ quick history and exam for transplant patients:

Kashlak Pearl: Check for hair growth in places you don’t want it (cyclosporine) and hair loss in places you do (tacrolimus → alopecia). Stick out hands for tremor (tacrolimus or cyclosporine), tongue for thrush and ask about diarrhea (mycophenolate level). Dr. Topf checks the gums for gingival hyperplasia and screens patients for skin cancer. 

Cyclosporine can also lead to lipid metabolism dysregulation and significant dyslipidemia in certain patients.

Diarrhea workup in the patient with kidney transplant:

Analogous to pneumonia in the HIV patient, common things are still common! The first consideration for diarrhea in a transplant patient should be the usual offenders (viral enteritis) Beyond those usual concerns,  C. diff is a common enteric pathogens, CMV colitis should be considered as well as non-infectious diarrhea  from MMF associated colitis, which can occur at any point in the patient’s course. To make things more complicated, infectious diarrhea can damage enterocytes, inhibit efflux of immunosuppressive agents like tacrolimus, resulting in further diarrhea / other symptoms!

In cases of MMF-associated diarrhea,  Dr. Farouk may lower the dose of MMF or switch to a different mycophenolate preparation (mycophenolate sodium). Monitor the Cr closely in patients with diarrhea as they are prone to volume depletion and AKI.

Post Transplant prophylaxis

CMV prophylaxis is continued for at least 3-6 months post-transplant based on risk, which is determined by the donor and recipient’s pre-transplant CMV status.

Some centers use 3 months of nystatin after transplant. Additionally, some centers prescribe lifelong TMP-SMX prophylaxis for Pneumocystis and Nocardia (this is what Dr. Farouk does in her practice).

Kashlak Pearl: Dr. Farouk notes TMP-SMX is effective for both Pneumocystis and Nocardia but carries with it a risk for hyperkalemia. If TMP-SMX is switched to dapsone, for example, due to renal side effects, the Nocardia coverage is lost.

Dr. Farouk cites an overall low risk for fracture in patients on prednisone 5 mg or less per day. Patients are often given calcium and vitamin D, but she notes the calcium can probably be dropped if there are no issues with hypocalcemia.

BK virus nephropathy can result from over-immunosuppression and is suspected based on rising virus levels in the blood. If this is identified, a reduction in immunosuppression may be indicated.

Kidney Transplant Rejection

Cellular (T cell) Rejection

Biopsy looks for inflammatory cells to characterize cellular rejection. Arteritis (involvement of the artery walls) is the most severe form. Treatment targets a decrease in T cell activity. One approach includes T cell depletion through antithymocyte immunoglobulin, essentially  “a nuclear bomb that gets rid of most of your T cells.”

Antibody Mediated (B cell) Rejection

Injury can be both complement mediated and complement independent. On biopsy the pathology ranges from acute tubular necrosis to thrombotic microangiopathy. They also look for complement deposition within the vasculature. Blood is sent for recipient antibodies against the donor’s specific HLA alleles. Treatment approaches may include immunosuppression with steroids, plasmapheresis or IVIG.

Banff Criteria/Classification 

Dr. Hiremath points out these criteria, from the Banff Foundation for Allograft Pathology, which are used to categorize renal allograft pathology. For those interested, there is a freely-available 2018 review by Roufosse et. al! 

Biopsy

One should suspect rejection in a patient with a rising Cr, increase in proteinuria or new hematuria. Dr. Farouk has a low threshold to biopsy, but notes that there is a high degree of interobserver variability between pathologists reviewing kidney biopsies for transplant rejection. Additionally, while overt/frank rejection may not be noted, oftentimes some useful information can be gleaned from biopsy that can result in changes/adjustments to therapy.

Complications after Kidney Transplant

Cardiovascular complications

Forty percent of patients die with a functioning graft, often from cardiovascular disease. Dr. Farouk mentions that there may be some use for SGLT-2 inhibitor drugs to help mitigate cardiovascular disease in these patients.

Dr. Farouk cites underlying comorbidities like Diabetes, Hypertension, Hyperlipidemia and eventual CKD that develops within the first decade after Kidney transplant as contributors to cardiac risk.

Statins are still recommended for all patients with kidney transplant by KDIGO, but the evidence is not strong.

Malignancy after Kidney transplant

Skin cancer screening: Non-melanoma skin cancers are the most common malignancy following kidney transplant —Voora AJKD 2019. Patients should have regular assessments at their nephrology appointments and yearly evaluations with dermatology (if not more regular). 

Colon cancer screening is recommended every 5 years at some centers (expert opinion).

Post-transplant Lymphoproliferative Disorder (PTLD)  can present in any organ. Not all PTLD is associated with EBV so don’t rule it out after a negative serology.

Recommended Reading & Works Referenced

Cimino FM¹, Snyder KA². Primary Care of the Solid Organ Transplant Recipient. Am Fam Physician. 2016 Feb 1;93(3):203-10.

https://www.ncbi.nlm.nih.gov/pubmed/26926613

Wong CJ¹, Pagalilauan G². Primary Care of the Solid Organ Transplant Recipient. Med Clin North Am. 2015 Sep;99(5):1075-103. doi: 10.1016/j.mcna.2015.05.002.

https://www.ncbi.nlm.nih.gov/pubmed/26320047

Primary Care of the Renal Transplant Patient. JGIM 2010 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881977/ 

Augustine J. Kidney transplant: New opportunities and challenges. Cleve Clin J Med. 2018;85(2):138-144.

https://pubmed.ncbi.nlm.nih.gov/29425089/?from_term=Kidney+Transplant&from_pos=1

Johnson C, Kaplan B. Biomarkers and Kidney Transplant: Time for a New Paradigm?. Transplantation. 2018;102(4):552-553.

https://pubmed.ncbi.nlm.nih.gov/29319617/?from_term=Kidney+Transplant&from_pos=7

Roufosse C, Simmonds N, Clahsen-van groningen M, et al. A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology. Transplantation. 2018;102(11):1795-1814.

https://journals.lww.com/transplantjournal/Fulltext/2018/11000/A_2018_Reference_Guide_to_the_Banff_Classification.14.aspx

Voora S, Adey DB. Management of Kidney Transplant Recipients by General Nephrologists: Core Curriculum 2019. Am J Kidney Dis. 2019;73(6):866-879.

https://www.ajkd.org/article/S0272-6386(19)30161-1/fulltext

Goal

Listeners will learn valuable skills to assist in the management and counseling of pre- and post- kidney transplant patients.

Learning objectives

After listening to this episode listeners will…  

1. Recognize the criteria for kidney transplant referral and evaluation, as well as the importance of referring a patient as soon as they are eligible. 
2. Be able to counsel a patient regarding what to expect before, during and after the transplant process.
3. Know the main classes of medication used after patients have received transplants, to include their side effects and any relevant monitoring. 
4. Be familiar with the different types of rejection, the clinical signs/symptoms of rejection and the utility / limitations of kidney biopsy.
5. Be able to discuss the post-transplant complications of kidney transplantation (cardiovascular, malignancy, etc.) as well as what type of prophylactic medications should be considered in these patients.

Disclosures

Drs. Cyrus Askin MD, Samira Farouk MD, Swapnil Hiremath MD, Jennie Lin MD & Matt Sparks MD report no relevant financial disclosures. Dr. Topf has received honoraria from Astra Zeneca and Cara Therapeutics. He is joint venture partner in Davita Dialysis centers receiving dividends.        

The Curbsiders report no relevant financial disclosures. 

Citation

Cyrus A, Topf J, Farouk S, Swapnil H, Lin J, Sparks M, Watto MF. “#210 NephMadness: Kidney Transplant for the Internist”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. April 27, 2020