Keratoplasty rejection after messenger RNA vaccine (BNT162b2) for COVID-19.

This report shows a case of corneal transplant rejection after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), short after receiving the BNT162b2 vaccine, in a patient who had undergone keratoplasty more than 20 years ago, with no previous episodes of rejection and no other factor that could lead to the findings on his examinations. After treatment with high doses of topic, oral, and sub-conjunctival corticoids, the patient had a favorable therapeutic response. The signs of corneal transplant rejection must be oriented to the patients and the causing factors actively searched by ophthalmologists so that treatment is rapidly initiated and sequels are avoided. This report raises the question if these events are correlated and whether the patient should receive the second dose of the vaccine against SARS-CoV-2 or not.

Acute Cellular Rejection in A Kidney Transplant Recipient Following Vaccination with Inactivated SARS-CoV-2 Vaccine.

SARS-CoV-2 vaccines are being administered worldwide. Most of the reported side effects are mild and self-limiting with few reported cases of severe adverse reactions. Here we report a case of acute cellular rejection in a kidney transplant recipient following vaccination with an inactivated SARS-CoV-2 vaccine. fifty- one years old man with autosomal dominant polycystic kidney disease, who had received a kidney transplantation from a living related donor, 3 years ago, presented with an impaired kidney function seven days after receiving the first dose of Sinovac's COVID-19 vaccine. Kidney transplant biopsy revealed acute cellular rejection. The allograft function completely recovered after treatment with steroids. The analysis and investigation of the complications and adverse reactions induced by anti-COVID-19 vaccines, could increase our understanding of the underlying pathogenesis.  DOI: 10.52547/ijkd.6915.

Pretransplant use of toripalimab for hepatocellular carcinoma resulting in fatal acute hepatic necrosis in the immediate postoperative period.

Immune checkpoint inhibitors are increasingly used in the treatment of various solid tumors, including hepatocellular carcinoma (HCC). For liver transplant recipients, the safety of using immune checkpoint inhibitors before or after transplantation remains to be further explored. Former reports were mainly about posttransplant use of immune checkpoint inhibitors resulting in allograft rejection. Here we present one HCC patient who received toripalimab (an immune checkpoint inhibitor currently in phase 3 clinical trial for HCC) therapy before undergoing liver transplantation. He finally suffered fatal acute hepatic necrosis which is likely to be related to the acute immune rejection caused by the pretransplant use of toripalimab.

Acute renal transplant rejection following nivolumab therapy for metastatic melanoma.

Cancers can develop the ability to evade immune recognition and destruction. Immune checkpoint inhibitors (ICIs) are drugs targeting these immune evasion mechanisms. ICIs have significantly improved outcomes in several cancers including metastatic melanoma. However, data on toxicities associated with allograft transplant recipients receiving ICI is limited. We describe a case of a 71-year-old woman who was diagnosed with metastatic melanoma 13 years after renal transplantation. She was commenced on the ICI nivolumab. She developed acute renal transplant rejection 15 days after administration of the first dose. She continues on haemodialysis but has demonstrated complete oncological response. This case demonstrates the risk of acute renal transplant rejection versus improved oncological outcomes. Patients and clinicians must consider this balance when initiating ICI therapy in allograft transplant recipients. Patients should be fully consented of the potential consequences of acute renal transplant rejection including lifelong dialysis.

Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation.

CD25, the alpha chain of the IL-2 receptor, is expressed on activated effector T cells that mediate immune graft damage. Induction immunosuppression is commonly used in solid organ transplantation and can include antibodies blocking CD25. However, regulatory T cells (Tregs) also rely on CD25 for their proliferation, survival, and regulatory function. Therefore, CD25-blockade may compromise Treg protective role against rejection. We analysed in vitro the effect of basiliximab (BXM) on the viability, phenotype, proliferation and cytokine production of Treg cells. We also evaluated in vivo the effect of BXM on Treg in thymectomized heart transplant children receiving BXM in comparison to patients not receiving induction therapy. Our results show that BXM reduces Treg counts and function in vitro by affecting their proliferation, Foxp3 expression, and IL-10 secretion capacity. In pediatric heart-transplant patients, we observed decreased Treg counts and a diminished Treg/Teff ratio in BXM-treated patients up to 6-month after treatment, recovering baseline values at the end of the 12-month follow up period. These results reveal that the use of BXM could produce detrimental effects on Tregs, and support the evidence suggesting that BXM induction could impair the protective role of Tregs in the period of highest incidence of acute graft rejection.

Pembrolizumab-induced severe rejection and graft intolerance syndrome resulting in renal allograft nephrectomy.

INTRODUCTION: Pembrolizumab is a selective anti-programmed cell death protein-1 (PD-1) humanized monoclonal antibody that inhibits PD-1 activity by binding to the PD-1 receptor that is found on activated T-cells. The goal of the treatment is to allow the immune system to target and destroy cancer cells by preventing cancer cells from binding to PD-1 receptors, leading to decreased tumor growth. The activation of T-cells by pembrolizumab not only leads to the destruction of malignant cells but also attacks the donor alloantigens that are present in a renal transplant, resulting in graft rejection. CASE REPORT: We present a case of a 46-year-old African American female with history of renal transplant who was treated with pembrolizumab for stage IV B endometrial adenocarcinoma and experienced renal transplant rejection and severe graft intolerance syndrome.Management and outcome: Due to ongoing graft intolerance, a transplant nephrectomy was performed. Allograft pathology was consistent with non-viable kidney with tubulitis, interstitial fibrosis and necrosis consistent with transplant rejection without any evidence of malignancy. DISCUSSION: As emphasized in our case, there is a very high risk of graft rejection in patients who need to be placed on immunomodulators such as pembrolizumab, so the risk versus benefit needs to be assessed and discussed. Our case is unique because pembrolizumab not only caused graft rejection but also severe graft intolerance syndrome which led to transplant nephrectomy. Further guidelines are needed in renal transplant patients requiring PD-1 inhibitors to establish the ideal treatment plan of immunosuppression management and anti-cancer treatments.

Tacrolimus trough levels higher than 6 ng/mL might not be required after a year in stable kidney transplant recipients.

BACKGROUND: Little is known regarding optimal tacrolimus (TAC) trough levels after 1 year post-transplant in stable kidney transplant recipients (KTRs) who have not experienced renal or cardiovascular outcomes. This study aimed to investigate the effect of 1-year post-transplant TAC trough levels on long-term renal and cardiovascular outcomes and opportunistic infections in stable KTRs. METHODS: KTRs receiving TAC with mycophenolate-based immunosuppression who did not experience renal or cardiovascular outcomes within 1 year post-transplant were enrolled from a multicenter observational cohort study. Renal outcome was defined as a composite of biopsy-proven acute rejection, interstitial fibrosis and tubular atrophy, and death-censored graft loss. Cardiovascular outcome was defined as a composite of de novo cardiomegaly, left ventricular hypertrophy, and cardiovascular events. Opportunistic infections were defined as the occurrence of BK virus or cytomegalovirus infections. RESULTS: A total of 603 eligible KTRs were divided into the low-level TAC (LL-TAC) and high-level TAC (HL-TAC) groups based on a median TAC level of 5.9 ng/mL (range 1.3-14.3) at 1 year post-transplant. The HL-TAC group had significantly higher TAC trough levels at 2, 3, 4, and 5 years compared with the levels of the LL-TAC group. During the mean follow-up of 63.7 ± 13.0 months, there were 121 renal outcomes and 224 cardiovascular outcomes. In multivariate Cox regression analysis, LL-TAC and HL-TAC were not independent risk factors for renal and cardiovascular outcomes, respectively. No significant differences in the development of opportunistic infections and de novo donor-specific anti-human leukocyte antigen antibodies and renal allograft function were observed between the two groups. CONCLUSIONS: TAC trough levels after 1 year post-transplant remained at a similar level until the fifth year after kidney transplantation and were not directly associated with long-term outcomes in stable Korean KTRs who did not experience renal or cardiovascular outcomes. Therefore, in Asian KTRs with a stable clinical course, TAC trough levels higher than approximately 6 ng/mL might not be required after a year of kidney transplantation.

Bilateral Corneal Graft Rejection Associated With Pembrolizumab Treatment.

PURPOSE: To report the first case of corneal graft rejection presumably associated with pembrolizumab immunotherapy. METHODS: Case report and literature review. RESULTS: An asymptomatic 85-year-old woman with a history of bilateral penetrating keratoplasty presented for a follow-up visit with bilateral diffuse keratic precipitates and subepithelial infiltrates. There were no anterior chamber cells. Bilateral subclinical corneal graft rejection was suspected. Three months previously, pembrolizumab immunotherapy was started for a metastatic urothelial cell tumor. Corneal graft rejection was managed with topical dexamethasone drops, which were tapered slowly. Pembrolizumab treatment was continued with careful ophthalmological follow-up. Unfortunately, recurrence of corneal graft rejection was observed 8 weeks after cessation of topical dexamethasone drops. After consulting the treating oncologist, pembrolizumab treatment was stopped to prevent recurrent corneal graft rejection. CONCLUSIONS: We report the first case of corneal graft rejection presumably associated with pembrolizumab immunotherapy. Corneal graft rejection may be successfully managed with corticosteroid therapy. However, constant vigilance and follow-up are advised because of the risk of recurrence in case of continued pembrolizumab treatment. Given the subclinical presentation, baseline ophthalmological screening is advised in all corneal graft patients after initiating immune checkpoint inhibitor therapy.

Renal Toxicity.

With the increasing use of immunotherapy, there has been an associated increased survival in many cancers but has also resulted in unregulated organ-specific toxicities. In this chapter, we discuss the renal toxicities associated with a checkpoint inhibitor (CPI) from the typical acute tubulointersitial nephritis to glomerulonephritis, their proposed mechanisms, and treatments. We also discuss the use of CPI and reactivation of preexisting auto-immune diseases and focus on renal cell cancer in setting of Chronic kidney disease (CKD). Transplant rejection in the setting of CPI use is yet to be further studied, and available data is presented in this chapter.

Comparison of Kidney Transplant Function, Lipid Metabolism Disorders, and Glucose and Hemoglobin Concentration in Transplant Patients Treated With Proliferation Signal Inhibitor (Everolimus) or Calcineurin Inhibitor (Tacrolimus).

INTRODUCTION: After kidney transplantation (KTx) in patients with diagnosed cancers, calcineurin inhibitor tacrolimus (TAC) is replaced by sirolimus or everolimus (EV). OBJECTIVE: The objective of the study was to compare the lipid metabolism parameters, KTx function, and glucose and hemoglobin (Hgb) levels in patients treated with EV to those on TAC. MATERIAL AND METHODS: The retrospective study included 114 patients: 54 (17 women and 37 men) aged 57.6 years (18-77 years) treated with EV and 60 (18 women and 42 men) aged 49.6 years (20-77 years) treated with TAC as a control group. Their total cholesterol (TC), triglycerides (TG), fasting glucose (FG), serum creatinine (SCr), Hgb, and estimated glomerular filtration rate (eGFR) were assessed. In the patients treated with EV, the above values were evaluated before conversion, as well as 12 and 24 months following the switch and were evaluated once in the group treated with TAC. RESULTS: In the EV-treated group, the mean preconversion values after 12 and 24 months were as follows: TC 5.06, 6.59, and 5.98 mmol/L; TG 1.90, 2.48, and 2.20 mmol/L; FG 94.95, 97.85, and 104.05 mg/dL; SCr 1.46, 1.44, and 1.56 mg/dL; Hgb 12.46, 12.83, and 13.36 g/dL; and eGFR 50.3, 50.6, and 50.5 mL/min/1.73 m2. In the patients on TAC, the authors obtained the following values: TC 4.6 mmol/L; TG 1.87 mmol/L; glucose 104.13 mg/dL; SCr 1.51 mg/dL; Hgb 13.96 g/dL; and eGFR 56.6 mL/min/1.73 m2. CONCLUSIONS: After conversion from TAC to EV, increased values of TC and TG were observed after 1 year, while the increased values of TC, TG, SCr, Hgb, and FG were observed after 2 years.

Use of Ipilimumab and Pembrolizumab in Metastatic Melanoma in a Combined Heart and Kidney Transplant Recipient: A Case Report.

New therapeutic agents such as checkpoint inhibitors are promising strategies in the treatment of metastatic melanoma. Transplant recipients are generally at higher risk of malign diseases. Limited data are available for the use and safety of these agents in this population. We describe a patient who had a stable transplant function over years after a combined heart and kidney transplantation. Immunosuppressive medications included tacrolimus and azathioprine and were later switched to sirolimus and azathioprine. Metastatic melanoma was diagnosed; after detailed explanation of the potential risk, the patient was initially treated with the anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab but experienced an acute kidney graft rejection and rapid progression. Rejection therapy with high-dose corticosteroids was successful, and kidney function was stabilized. Because of the urgent request of the patient for additional therapy, he received a PD-1 inhibitor. Acute kidney graft rejection resulted, with indication for acute dialysis. He developed severe candida pneumonia and died despite extensive antimicrobial therapy. Checkpoint inhibitors have become the standard in a broad entity of tumors. Organ transplant patients are at higher risk of developing malignant diseases. Limited data are available for the use of checkpoint inhibitors in this subgroup, and the use of checkpoint inhibitors is associated with a high risk of graft rejection.

Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do?

Immune checkpoint inhibitors have dramatically improved cancer therapy for many patients. These humanized monoclonal antibodies against various immune checkpoints (receptors and ligands) effectively treat a number of malignancies by unleashing the immune system to destroy cancer cells. These drugs are not excreted by the kidneys or liver, have a long half-life, and undergo receptor-mediated clearance. Although these agents have greatly improved the prognosis of many cancers, immune-related end organ injury is a complication that has come to light in clinical practice. Although less common than other organ involvement, kidney lesions resulting in acute kidney injury and/or proteinuria are being described. Acute tubulointerstitial nephritis is the most common lesion seen on kidney biopsy, while acute tubular injury and glomerular lesions occur less commonly. Clinical findings and laboratory tests are suboptimal in predicting the underlying renal lesion, making kidney biopsy necessary in the majority of cases to definitely diagnose the lesion and potentially guide therapy. Immune checkpoint inhibitor discontinuation and corticosteroid therapy are recommended for acute tubulointerstitial nephritis. Based on a handful of cases, re-exposure to these drugs in patients who previously developed acute tubulointerstitial nephritis has been mixed. Although it is unclear whether re-exposure is appropriate, it should perhaps be considered in patients with limited options. When this approach is taken, patients should be closely monitored for recurrence of acute kidney injury. Treatment of cancer in patients with a kidney transplant with immune checkpoint inhibitors risks the development of acute rejection in some patients and requires close surveillance.

The successful use of pembrolizumab in a renal transplant recipient with metastatic melanoma.

We report a case in which a renal transplant recipient with metastatic melanoma had an excellent response to treatment with second line programmed cell death protein 1 (PD-1) inhibitor therapy, pembrolizumab. Acute cellular allograft rejection on initiation of PD-1 inhibitor was successfully reversed with methylprednisolone. By converting the patient to sirolimus and giving predose prednisolone, pembrolizumab was continued with stable renal function and an excellent oncological response. This case supports the efficacy of PD-1 inhibitors in patients who are chronically immunosuppressed, and suggests an approach to maintain transplant function.

Liver graft rejection following immune checkpoint inhibitors treatment: a review.

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a variety of solid tumors; nonetheless, they have not been well investigated and are still recognized as a relative contraindication for patients with a liver transplantation (LT) history, since ICIs treatment might potentially lead to graft rejection. The program death-1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways are implicated in the tolerance of transplanted organ, as well as blockade of the pathways, which contribute to eliminating tumors and may inadvertently lead to peripheral transplant rejection. Currently, no guidelines are available regarding the treatment for ICIs patients with a prior LT history. Therefore, this study was carried out to review the recent studies, attempting to introduce the ICIs-related graft rejection after LT from various aspects. We believed that ICIs could be given for the well-informed patients receiving LT and developed recurrence in a controlled setting. Typically, these patients should be treated according to a clinical care path or a prospective clinical trial, so as obtain a persistent anti-tumor immune response in the meantime of avoiding graft rejection, adjust the immunosuppression, reduce the possibility of graft loss following rejection, and have the opportunity to develop biomarkers for tumor response and transplant rejection.

Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature.

BACKGROUND: Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT. METHODS: Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs. RESULTS: Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14-79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92-32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3-22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs. CONCLUSIONS: SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients.

Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue.

BACKGROUND: It is well known that the state of immune tolerance induced by broad immunosuppression to prevent allograft rejection leads to an increased risk of the development of cancer. One of the most promising new areas of cancer treatment has been the development of immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1/programmed death-ligand 1 (PD-L1) pathways. As a logical consequence, growing interest in these agents translated into their implementation in patients with transplant-related malignancies. Because of overlapping and perhaps mutually exclusive mechanisms of action of transplant immunosuppression and cancer immunomodulation, it is critical to examine these interactions. MATERIALS AND METHODS: We carried out a systematic search for review articles and case reports published between July 2014 and November 2017 using three engines: Usearch, PubMed, and Up-to-date. RESULTS: Overall, there were 20 cases with 12 allograft rejections. The rejection rate associated with nivolumab was 73% (8/11) and with pembrolizumab it was 100% (2/2). The use of ipilimumab did not lead to rejection in any instance (0/4, 0%). Of the two patients treated with the sequential use of ipilimumab/nivolumab, one lost his allograft, yielding a rejection rate of 50%. The sequential use of ipilimumab/pembrolizumab led to a rejection rate of 100% (1/1, 100%). CONCLUSION: The use of agents that act on the PD-L1 pathway are contraindicated in the face of solid organ allografts because of unacceptably high rates of irreversible allograft rejection. It appears that the use of ipilimumab may be tolerated as the mechanism is different from that of the PD-L1 agents. IMPLICATIONS FOR PRACTICE: Transplant rejection is a complex process that puts stress on patients and their families and can lead to tragic results. Significant advancements in the field of immunosuppression have led to the engenderment of agents devised to extend the survival of transplant recipients. The advent of immunomodulators in cancer therapy has been paradigm-shifting; however, because of their mechanism of action, their use must be carefully considered in patients with allografts and concomitant cancer. It appears that ipilimumab can be administered safely in these patients but that agents acting on the programmed death-ligand 1 pathway are contraindicated because of high rates of irreversible rejection.

Increase in short-term risk of rejection in heart transplant patients receiving granulocyte colony-stimulating factor.

BACKGROUND: Neutropenia is a significant adverse event after heart transplantation (HT) and increases infection risk. Granulocyte colony-stimulating factor (G-CSF) is commonly used in patients with neutropenia. In this work, we assessed the adverse effects of G-CSF treatment in the setting of a university hospital. METHODS: Data on HT patients from January 2008 to July 2016 were reviewed. Patients who received G-CSF were identified and compared with patients without a history of therapy. Baseline characteristics, rejection episodes, and outcomes were collected. Data were analyzed by incidence rates, time to rejection and survival were analyzed using Kaplan-Meier curves, and odds ratios were generated using logistic regression analysis. RESULTS: Two hundred twenty-two HT patients were studied and 40 (18%) received G-CSF for a total of 85 total neutropenic events (0.79 event/patient year). There were no differences in baseline characteristics between the groups. In the 3 months after G-CSF, the incidence rate of rejection was 0.067 event/month. In all other time periods considered free of G-CSF effect, the incidence rate was 0.011 event/month. This rate was similar to the overall incidence rate in the non-GCSF group, which was 0.010 event/month. There was a significant difference between the incidence rates in the G-CSF group at 0 to 3 months after G-CSF administration and the non-GCSF group (p = 0.04), but not for the other time periods (p = 0.5). Freedom from rejection in the 3 months after G-CSF administration was 87.5% compared with 97.5% in the non-GCSF group (p = 0.006). CONCLUSIONS: G-CSF administration was found to be associated with significant short-term risk of rejection. This suggests the need for increased surveillance during this time period.