By: Omar Elhoriny, PharmD Candidate c/o 2024 and Nancy Yousry, PharmD Candidate c/o 2024

The therapeutic space of solid organ transplantation holds great relevance to practicing pharmacists and yet is rarely a topic of discussion in didactic teaching. The field of renal transplant therapeutics has made remarkable strides over the years, offering new hope to patients suffering from end-stage renal disease. Pharmacists play a pivotal role in ensuring the success of renal transplant procedures, as their expertise extends beyond medication dispensing to encompass pre- and post-transplant services. In this article, we will explore the critical role of pharmacists in renal transplant care and the evolving landscape of allograft rejection management.

Understanding Renal Transplantation

Renal transplantation is often considered the optimal treatment for patients with end-stage renal disease, providing improved quality of life and extended longevity. However, the success of a renal transplant heavily depends on preventing and managing complications, such as allograft rejection.

Patients are typically eligible for renal transplantation if they have end-stage renal disease on dialysis or chronic kidney disease approaching the need for dialysis.¹ End-stage renal disease is characterized by an estimated glomerular filtration rate (eGFR) of less than 15 mL/min, and its causes include diabetic nephropathy, hypertension, lupus, and nephrotic syndrome.² There are several contraindications that prevent certain patients from receiving a new kidney, including metastatic cancer, unresolved active infection, inability to receive surgery due to respiratory or cardiovascular complications, early loss of two previous transplants, or existing unstable mental health conditions.³

Many factors come into play when predicting a transplant’s success in a patient, one being the kidney donor profile index (KDPI). KDPI is a measurement that assesses a donor’s kidney to predict the likelihood of graft failure.⁴ A lower KDPI score signifies that the kidney will function longer. For instance, a donated kidney with a score of 10% will have a shorter longevity than 10% of all donated kidneys but a longer longevity than 90% of all donated kidneys.⁴ Another testing method used is calculated panel reactive antibodies (CPRA), which determines the compatibility between a recipient and a donor based on the presence of specific human leukocyte antigen (HLA) antibodies a candidate may possess.⁵ Renal allograft rejection is mediated by immune recognition of the donated kidney’s non-self (foreign) antigens. Past exposure to foreign HLA, such as a history of pregnancy or blood transfusion, leads to HLA sensitization, which may bode poorly for graft survival. A CPRA involves testing a candidate’s serum against lymphocytes from a panel of about 100 blood donors. The blood donors represent the HLA makeup from a donor in that area. If there is no reaction between a candidate’s serum and samples, the candidate is not HLA sensitized and has a CPRA of 0.⁵ If a candidate’s serum reacts with a certain number of samples, their CPRA is that corresponding percentage (e.g., 60 samples out of 100 corresponds to a CPRA of 60%). A higher percentage of CPRA means a higher chance of acute rejection. KDPI, CPRA, and concomitant diseases like diabetes elevate the chance of graft failure, usually immediately after transplantation. This acute failure is known as delayed graft function (DGF). Appearing as a manifestation of acute kidney injury post-transplantation, DGF is usually defined by the need for dialysis within the first week after transplant surgery. Poor kidney function within the first week and beyond may be an indicator of poor longevity of the graft.⁶ Characteristics of the donor kidney itself, such as ischemic time, may be possible contributors. Ischemic time is the period in which the donated organ is not receiving blood, and therefore oxygen, before being transplanted. Warm ischemic time refers to the time between the removal of the organ and storage in ice. Cold ischemic time is the amount of time spent in ice storage. A warm ischemic time of at least 30 minutes corresponds to more tissue damage than a cold ischemic time of more than 24 hours.⁷ DGF can be perpetuated by a prolonged ischemic time, both warm and cold. The cause of death from deceased donors also plays a role in DGF. Donations after cardiac death (DCD) transplants have a higher chance for DGF compared to standard-criteria donors (42 to 51% and 24%, respectively).⁶

The Pharmacist’s Role

The selection process for transplant patients is rigorous and involves a multidisciplinary team of surgeons, social workers, nurses, nutritionists, nephrologists, pharmacists, and others. Not only are patients assessed on their likelihood of experiencing rejection, but they are also evaluated by social factors like adequate support systems and medication adherence.⁸ Pharmacists are critical members of the transplant team who help discern a patient’s candidacy, treatment, and monitoring in the acute phase after surgery and beyond.

Transplant pharmacists present their objective assessments at the multidisciplinary patient selection meeting.⁸ They assess the patient’s medication history for drug interactions and other possible concerns. Many of the maintenance immunosuppressive drugs used in the transplant setting interact with CYP3A4-interacting drugs (e.g., azole antifungals, verapamil, phenytoin, rifampin, and cyclosporine). It is also common for transplant pharmacists to speak with candidates and conduct medication reconciliations to assess health literacy and adherence. It is imperative for transplant candidates to prove their adherence as the immunosuppressive regimen post-surgery will be a lifelong treatment. Transplant pharmacists also conduct educational sessions for patients when their surgery date grows near. Such education covers the medications they will be on after surgery and the associated risks. Post-operative responsibilities encompass routine laboratory checks and constant monitoring of the several medications patients will be started on. Monitoring is very critical in post-operative transplant patients as any changes in electrolytes or increases in creatinine may be signs of DGF. Generally, the transition of care from inpatient transplantation to routine post-transplantation clinic visits is a critical duty for transplant pharmacists.⁸

Allograft Rejection Diagnosis

Diagnosing allograft rejection is a complex process, but it is an area where pharmacists can make a significant impact.  Transplantation rejection can be classified into three categories: hyperacute, acute, and chronic. Hyperacute rejection is caused by specific antibodies against the graft and occurs within minutes or hours after grafting. Acute rejection occurs days or weeks after transplantation and can be caused by specific lymphocytes in the recipient that recognize human leukocyte antigens in the tissue or organ grafted. Finally, chronic rejection usually occurs months or years after organ or tissue transplantation.⁹ Chronic allograft rejection is caused by the development of interstitial fibrosis/tubular atrophy (IF/TA), previously known as chronic allograft nephropathy (CAN). Several pathophysiological mechanisms, such as inflammation and activation of renal fibroblasts, have been associated with IF/TA.¹⁰

Diagnostic Markers

Useful laboratory markers that assist in the recognition of allograft rejection involve the collection of various laboratory values which include urine sampling, complete blood cell count, histological studies, as well as HLA typing for assessment of histocompatibility between donor and recipes, as well as serology testing for HIV, hepatitis B, and hepatitis C.¹¹

Acute Rejection Treatment Approach

The treatment of organ rejection depends on the type of injury. Comorbid complications, such as arterial hypertension, pulmonary edema, and uremia, can be involved in chronic kidney rejection. Thus, the required treatment involves hemodialysis, hemofiltration, and the use of diuretics. The approach to treatment for the transplant recipient with acute rejection relies on accurate diagnosis and classification of the immunologic pathology. Treatment strategies differ between T cell-mediated rejection and antibody-mediated rejection and the aggressiveness of such treatment on a case-to-case basis.¹² Once non-immunologic causes of acute rejection are ruled out, allograft biopsy and donor-specific antigen (DSA) assessments should be performed to determine treatment approach.¹² Information on potential treatment options for acute rejection can be found in Table 1, and an algorithm for the treatment of acute rejection can be found in Figure 1.

In situations where a biopsy is attained and a cellular T cell-mediated rejection is determined, intravenous steroids and the usage of anti-thymocyte globulin are involved. However, when antibody-mediated rejection is diagnosed, plasma exchange and immunoglobulin (IG) are also proposed as treatment pathways.¹²

By contrast, when the biopsy is found to not be safe or feasible, treatment approaches empirically involve Solu-Medrol (methylprednisolone), yet further interventions are stratified based on acute kidney injury (AKI) status. If a patient’s status of AKI is resolved, monitoring of graft function and optimization of immunotherapy is warranted, along with a confirmation that the patient has tested negative for DSA. If a patient’s AKI status is unresolved, anti-thymocyte globulin and intravenous IG are also recommended.¹²

Conclusion

Pharmacists play a critical role as part of the interdisciplinary team, attending to the needs of patients on an individualized basis for optimization of therapeutic benefit while minimizing harm in efforts to ensure survival for patients post allograft rejection. Several medication approaches have been studied and found to be useful based on differential diagnoses of the type of rejection. Further research is being conducted to define the qualitative guidelines that determine the trajectory of kidney transplant post-allograft rejection.

References

1. Kidney transplant. Cleveland Clinic. Updated March 14, 2022. Accessed September 25, 2023. https://my.clevelandclinic.org/health/treatments/22537-kidney-transplant.
2. End-stage renal disease (ESRD). Johns Hopkins Medicine. Accessed September 25, 2023. https://www.hopkinsmedicine.org/health/conditions-and-diseases/end-stage-renal-disease-esrd.
3. Abramowicz D, Cochat P, Claas FH, et al. European Renal Best Practice Guideline on kidney donor and recipient evaluation and perioperative care. Nephrol Dial Transplant. 2015;30(11):1790-1797. Doi:10.1093/ndt/gfu216
4. Kidney donor profile index (KDPI) guidelines for clinicians. Organ Procurement and Transplantation Network, Health Resources and Services Administration, U.S. Department of Health & Human Services. Accessed September 25, 2023. https://optn.transplant.hrsa.gov/professionals/by-topic/guidance/kidney-donor-profile-index-kdpi-guide-for-clinicians/.
5. About CPRA. Organ Procurement and Transplantation Network, Health Resources and Services Administration, U.S. Department of Health & Human Services. Accessed September 25, 2023. https://optn.transplant.hrsa.gov/data/allocation-calculators/about-cpra/.
6. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant. 2011;11(11):2279-2296. doi:10.1111/j.1600-6143.2011.03754.x
7. Schröder-Bergmann SL. Ischemia Time. Altmeyers Encyclopedia. Last Updated October 29, 2020. Accessed October 9, 2023. https://www.altmeyers.org/en/internal-medicine/ischemia-time-139040.
8. Maldonado AQ, Hall RC, Pilch NA, et al. ASHP Guidelines on Pharmacy Services in Solid Organ Transplantation. Am J Health Syst Pharm. 2020;77(3):222-232. Doi:10.1093/ajhp/zxz291
9. 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. doi:10.1097/TP.0000000000002366
10. Li X, Zhuang S. Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation. Fibrogenesis Tissue Repair. 2014;7:15. Published 2014 Oct 2. doi:10.1186/1755-1536-7-15
11. Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ. Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies. Front Med (Lausanne). 2019;5:358. Published 2019 Jan 8. doi:10.3389/fmed.2018.00358
12. Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020;15(3):430-438. doi:10.2215/CJN.11991019

Published by Rho Chi Post