A systematic review of opioid use and multimodal strategies in solid organ transplant recipients and living donors.

The opioid epidemic has impacted analgesia in the postoperative period for solid organ transplant (SOT) donors and recipients. However, optimal pain management and opioid stewardship strategies have not been identified across this unique population. The purpose of this systematic review was to evaluate the impact of perioperative opioid use and to describe multimodal analgesic strategies to reduce opiate use in SOT recipients and living donors. A systematic review was conducted. Electronic searches were performed in Medline, Embase, Google Scholar, and Web of Science through December 31, 2021. Title and abstracts were screened. Relevant articles underwent full-text review. Literature was separated into effects of opioid exposure on post-transplant outcomes, recipient pain management strategies, and living donor pain management strategies. Search yielded 25,190 records, and 63 were ultimately included. The impact of opioid use on post-transplant outcomes was assessed in 19 publications. The risk of graft loss in pretransplant opioid users was assessed in six reports and was found to be higher in the majority (66%) of publications. Opioid minimization strategies were reported in 20 studies in transplant recipients. Twenty-four studies evaluated pain management strategies in living donors. Both populations used a combination of multimodal strategies to minimize opioid use throughout the hospitalization and on discharge. Opioids are associated with select negative outcomes in post-transplant recipients. To minimize their use while also maintaining appropriate analgesia, multimodal pain regimens should be considered in SOT recipients and donors.

Use of hepatitis B viremic donors in kidney transplant recipients: A single center experience.

Utilization of Hepatitis B virus (HBV)-infected kidney allografts represents an opportunity to bridge the gap between organ supply and demand. Highly efficacious vaccines and antiviral therapies allow these allografts to be transplanted with negligible risk to the recipient. The purpose of this study was to describe the prophylactic strategies and related clinical outcomes of kidney transplant recipients who received a kidney from an HBV viremic donor. Eight patients received an allograft from an HBV viremic deceased kidney donor between January 1, 2017 and December 4, 2020. All recipients were immune to hepatitis B with a surface antibody titer greater than or equal to 10 mIU/ml (range: 12 - > 1000 mIU/ml). After transplant, 62.5% demonstrated HBV core antibody seroconversion at an average of 47.4 ± 28.5 days post-transplant. Anti-viral prophylaxis was initiated in 87.5% of patients; 62.5% preemptively during the transplant admission (range 1-3 days post-transplant) and 25% following HBcAb seroconversion (range 45-304 days post-transplant). Of the four patients who were started on entecavir preemptively, two subsequently core converted. These two patients had an HBV surface antibody less than 100 mIU/ml at the time of transplant. None of the recipients converted to HBV surface antigen positivity. The average estimated glomerular filtration rate was 41 ± 19 ml/min/1.73m2 , and there were no significant elevations in liver enzymes through one year post-transplant. The use of HBV viremic kidney allografts may represent an additional source of transplant organs; however, more studies are needed to better elucidate the optimal protective strategies for these recipients.

Initial experience of bamlanivimab monotherapy use in solid organ transplant recipients.

The widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to propagate the coronavirus disease 2019 (COVID-19) pandemic with solid organ transplant (SOT) recipients being an exceptionally vulnerable population for poor outcomes. Treatments for COVID-19 are limited; however, monoclonal antibodies are emerging as a potential therapeutic option to change the trajectory of high-risk patients. This retrospective single center cohort study evaluated the outcomes of SOT recipients with mild to moderate COVID-19 who received bamlanivimab monotherapy. Eighteen SOT recipients (15 kidney, 2 liver, and 1 heart) received the medication between November 9, 2020 and February 10, 2021 with no reported infusion reactions. One patient experienced headache and fatigue following the infusion that resolved within 3 days. Fourteen patients continued their recovery as an outpatient with no further escalation in care. Three patients required hospitalization: two for suspected bacterial pneumonia 9 and 32 days postinfusion, respectively, and one for acute kidney injury 7 days postinfusion. One patient had an emergency room visit for gastrointestinal symptoms 24 days postinfusion. In this small cohort of SOT recipients, bamlanivimab monotherapy appeared to be a well-tolerated option for treatment of mild to moderate COVID-19, but it was not completely effective in preventing hospitalization. One month following the end of this cohort, COVID-19 treatment guidance changed due to the rising prevalence of resistant variants. For this reason, bamlanivimab is now recommended to be used only in combination with etesevimab. Further studies are needed to fully elucidate the role of this therapy in SOT recipients.

Evaluation of a multimodal analgesic regimen on outcomes following laparoscopic living donor nephrectomy.

Postoperative pain is a significant source of morbidity in patients undergoing living donor nephrectomy (LDN) and a deterrent for candidates. We implemented a standardized multimodal analgesic regimen, which consists of pharmacist-led pre-procedure pain management education, a combination transversus abdominis plane and rectus sheath block performed by the regional anesthesia team, scheduled acetaminophen and gabapentin, and as-needed opioids. This single-center retrospective study evaluated outcomes between patients undergoing LDN who received a multimodal analgesic regimen and a historical cohort. The multimodal cohort had a significantly shorter length of stay (LOS) (days, mean ± SD: 1.8 ± 0.7 vs. 2.6 ± 0.8; p < .001) and a greater proportion who were discharged on postoperative day (POD) 1 (38.6% vs. 1.5%; p < .001). The total morphine milligram equivalents (MME) that patients received during hospitalization were significantly less in the multimodal cohort on POD 0-2. The outpatient MME prescribed through POD 60 was also significantly less in the multimodal cohort (median [IQR]; 180 [150-188] vs. 225 [150-300]; p < .001). The mean patient-reported pain score (PRPS) was significantly lower in the multimodal cohort on POD 0-2. The maximum PRPS was significantly lower on POD 0 (mean ± SD: 7 ± 2 vs. 8 ± 1, respectively; p = .02). This study suggests that our multimodal regimen significantly reduces LOS, PRPS, and opioid requirements and has the potential to improve the donation experience.

Acute Myeloid Leukemia Presenting Less Than 3 Weeks After Living Donor Kidney Transplant: A Case Report.

Acute myeloid leukemia (AML) is a rare malignancy with increased incidence in the kidney transplantation (KT) population for which immunosuppression has been implicated as a putative cause. The average time interval from KT to AML development is 5 years. We present the case of a 61-year-old man who was found to have peripheral blood blasts on a postoperative day 20 routine blood draw after an uneventful unrelated living donor kidney transplant. He subsequently had a bone marrow biopsy and next-generation sequencing (NGS)-based molecular testing, which demonstrated AML characterized by SMC1A and TET2 mutations. He received induction chemotherapy followed by hematopoietic cell transplantation (HCT) from the kidney donor, who happened to be matched at one haplotype. At 12 months after his HCT and 15 months after his KT, his AML remained in remission, normal renal function was preserved, no active graft-versus-host disease was present, and immunosuppression was tapering. With full donor-derived hematopoietic chimerism, we expect to be able to discontinue immunosuppression shortly, thereby achieving tolerance. The short time interval between KT and development of AML suggests the malignancy was likely present before KT. Modern NGS-based analysis offers a promising method of identifying transplant candidates with unexplained hematologic abnormalities on pre-KT testing who may benefit from formal hematologic evaluation.

Evaluation of cytomegalovirus prophylaxis in low and intermediate risk kidney transplant recipients receiving lymphocyte-depleting induction.

Cytomegalovirus (CMV) is a significant cause of morbidity in kidney transplant recipients (KTR). Historically at our institution, KTR with low and intermediate CMV risk received 6 months of valganciclovir if they received lymphocyte depleting induction therapy. This study evaluates choice and duration of CMV prophylaxis based on donor (D) and recipient (R) CMV serostatus and the incidence of post-transplant CMV viremia in low (D-/R-) and intermediate (R+) risk KTR receiving lymphocyte-depleting induction therapy. A protocol utilizing valacyclovir for 3 months for D-/R- and valganciclovir for 3 months for R+ was evaluated. Adult D-/R- and R+ KTR receiving anti-thymocyte globulin, rabbit or alemtuzumab induction from 8/20/2016 to 9/30/2018 were evaluated through 1 year post-transplant. Patients were excluded if their CMV serostatus was D+/R-, received a multi-organ transplant, or received basiliximab. Seventy-seven subjects met the inclusion criteria: 25 D-/R- (4 historic group, 21 experimental group) and 52 R+ (31 historic, 21 experimental). No D-/R- patients experienced CMV viremia. Among the R+ historic and experimental groups, there was no significant difference in viremia incidence (35.5% vs 52.4%; P = .573). Of these cases, the peak viral load was similar between the groups (median [IQR], 67 [<200-444] vs <50 [<50-217]; P = .711), and there was no difference in the incidence of CMV syndrome (16.1% vs 14.3%; P = 1.000) or CMV related hospitalization (12.9% vs 14.3%; P = 1.000). No patient experienced tissue invasive disease. These results suggest limiting valganciclovir exposure may be possible in low and intermediate risk KTR receiving lymphocyte-depleting induction therapy with no apparent impact on CMV-related outcomes.

Opioid Avoidance in Liver Transplant Recipients: Reduction in Postoperative Opioid Use Through a Multidisciplinary Multimodal Approach.

The prevalence of substance use disorder in the liver transplantation (LT) population makes postoperative pain management challenging. We report our initial experience with a novel, comprehensive, multidisciplinary opioid avoidance pathway in 13 LT recipients between January 2018 and September 2019. Patients received comprehensive pre-LT education on postoperative opioid avoidance by the surgeon, pharmacist, and psychologist at the time of listing. Immediately after LT, patients received a continuous incisional ropivacaine infusion, ketamine, acetaminophen, and gabapentin as standard nonopioid medications; rescue opioids were used as needed. We compared outcomes with a historical cohort of 27 LT recipients transplanted between August 2016 and January 2018 managed primarily with opioids. On average, opioid avoidance patients used 92% fewer median (interquartile range [IQR]) morphine milligram equivalents (MMEs) versus the historical cohort (7 [1-11] versus 87 [60-130] MME; P < 0.001) per postoperative day over a similar length of stay (8 [7-10] versus 6 [6-10] days; P = 0.14). Fewer outpatient MMEs were prescribed within the first 60 days after LT in the opioid avoidance group versus the historical cohort: 125 (25-150) versus 270 (0-463) MME (P = 0.05). This proof-of-concept study outlines the potential to profoundly reduce opioid utilization in the LT population using a comprehensive multidisciplinary approach.

Incidental COVID-19 in a heart-kidney transplant recipient with malnutrition and recurrent infections: Implications for the SARS-CoV-2 immune response.

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

Successful management of noncirrhotic hyperammonemia syndrome after kidney transplantation from putative Ureaplasma infection.

Noncirrhotic hyperammonemia (NCH) is a rare but often fatal complication of solid organ transplantation. We present a case wherein an infectious cause of NCH was suspected following kidney transplantation (KT) and the patient was promptly started on empirical antibiotic treatment which proved to be lifesaving. A 56-year-old Chinese woman with a past medical history of end-stage renal disease secondary to ischemic nephropathy and cerebrovascular accident received a kidney from a 52-year-old brain-dead donor with a Kidney Donor Profile Index score of 70%. She experienced immediate graft function and was discharged on post-operative day (POD) 4. On POD 10, she presented with a fever, acute onset of confusion, and abdominal pain. Her mental status deteriorated and required emergent intubation. Empiric broad-spectrum antibiotics were initiated. On hospital day 3, a serum ammonia was 889 µmol/L (normal <53 µmol/L). A urine sample was sent for Ureaplasma polymerase chain reaction (PCR) testing, and moxifloxacin and doxycycline were empirically started. Her ammonia rapidly normalized, and her mental status improved 48 hours after antibiotic initiation. She was extubated 5 days into treatment and was discharged after an 11-day hospitalization. Following discharge, her urine test resulted positive for Ureaplasma parvum or Ureaplasma urealyticum DNA detection with the 16S rRNA gene amplification probe. Mental status changes and hyperammonemia in the first 30 days post-KT should raise suspicion for NCH, and prompt empiric treatment with antimicrobials covering Ureaplasma and Mycoplasma should be considered.

Deceased donor kidney transplant complicated by spontaneous rupture of native kidney in a HIV patient.

Spontaneous native kidney rupture (SNKR) is a rare occurrence, commonly associated with underlying renal tumors or acquired renal cystic disease in both the kidney transplant (KT) and non-KT populations. Herein, we present a 65-year-old African American man who experienced a non-malignant SNKR 6 days after a deceased donor KT and underwent emergent native nephrectomy. The patient's hospital course was complicated by thrombocytopenia and refractory hypertension. He experienced delayed graft function and was maintained on hemodialysis until post-operative day 30. This case demonstrates an unusual presentation of SNKR in the immediate post-KT setting and illustrates the clinical decision-making algorithm.

Compound Effect of Kidney Donor Profile Index and Cold Ischemic Time on 1-Year Kidney Transplant Recipient Outcomes.

OBJECTIVE: Kidney Donor Profile Index (KDPI) and cold ischemic time (CIT) independently influence recipient outcomes after kidney transplantation; however, the compound effect of these variables on posttransplant outcomes is unknown. DESIGN: The Scientific Registry of Transplant Recipients database of deceased-donor kidney transplant recipients between January 2012 and December 2016 was reviewed. Recipients were stratified based on their KDPI (0%-20%, 21%-85%, 86%-100%) and then based on CIT (0-12, 13-24, 25-30, 31-36, ≥ 37 hours). The primary outcome is 1-year allograft loss. Secondary outcomes include primary nonfunction, delayed graft function, biopsy-proven rejection, and 1-year recipient mortality. RESULTS: Allograft loss was not affected by CIT for KDPI 0% to 20% (P = .898) or KDPI 86% to 100% (P = .731), but was significantly different for KDPI 21% to 85% (P < .001). The KDPI 21% to 85% group was the only group with a significant difference in primary nonfunction, demonstrating a linear rise with increasing CIT (P < .001). CIT did not affect recipient mortality for any KDPI group (KDPI 0%-20%, P = .306; KDPI 21%-85%, P = .098; KDPI 86%-100%, P = .774). Incidence of delayed graft function was greater for each KDPI group (P < .001) with increased CIT. Biopsy-proven rejection was not affected by CIT for KDPI 21% to 85% (P = .244) or KDPI 86% to 100% (P = .946). For KDPI 0% to 20%, there was a significant difference (P = .024); however, the incidence was not linear with increasing CIT. For the KDPI 86% to 100% group, incidence of mortality, allograft loss, primary nonfunction, and biopsy-proven rejection did not differ between CIT groups. CONCLUSIONS: Extended CIT alone should not hinder utilization of higher KDPI organs.

Implementation of a Multimodal Pain Management Order Set Reduces Perioperative Opioid Use after Liver Transplantation.

STUDY OBJECTIVE: Nonopioid strategies to optimize pain management in patients after liver transplantation remain underexplored. The purpose of this study was to evaluate whether the use of a multimodal pain management (MPM) order set would reduce postoperative opioid use in adult patients after liver transplantation. DESIGN: Retrospective pre- and post-order set implementation study. SETTING: Large academic tertiary care hospital. PATIENTS: Thirty-one adults who underwent liver transplantation were included; of these, 18 received provider-managed pain regimens (pre-MPM group: August 20, 2016-January 17, 2018), and 13 received the MPM order set (post-MPM group: January 18-July 31, 2018) after implementation of the order set on January 18, 2018. MEASUREMENTS AND MAIN RESULTS: The MPM order set included standardized receipt of acetaminophen 650 mg every 6 hours, gabapentin 300 mg every 8 hours (adjusted for renal function), and opioids for breakthrough pain. Patients managed with the MPM order set received, on average, 30.6 fewer opioid morphine milligram equivalents per day after final extubation than patients who did not receive MPM (median 16, interquartile range [IQR] 4.5-45.6 vs median 46.6, IQR 30.1-75.2; Mann-Whitney U test, p=0.031). Although patients in the post-MPM group had significantly worse renal function at baseline, no other statistically significant differences in baseline characteristics, pain scores, or prescribed outpatient opioids were noted between groups. Patients in the pre-MPM group had a shorter intensive care unit and overall length of stay; however, patients in the post-MPM group may have had more complex postoperative courses contributing to these differences. CONCLUSION: Implementation of the MPM order set significantly reduced postoperative opioid use in liver transplant recipients. Our results provide a compelling rationale to further investigate the use of a non-opioid-centered strategy to optimize pain management in patients recovering from liver transplantation, a population vulnerable to the risks of opioid use such as opioid use disorder, increased susceptibility to adverse effects, and poor allograft and survival outcomes.

Aggressive Epstein-Barr virus-negative B-cell post-transplant lymphoproliferative disorder in a hepatitis C-negative liver transplant recipient who received a hepatitis C-positive graft: Implications for D+/R- hepatitis C virus seroconversion.

Post-transplant lymphoproliferative disorder (PTLD) is an uncommon, but well-described complication after liver transplantation. Most recently, Hepatitis C virus (HCV) has been implicated in the development of PTLD. A HCV-negative 62-year-old man with autoimmune hepatitis received a HCV nucleic acid amplification test-positive liver graft from a 73-year-old brain-dead donor (D+/R-). After his recovery from the operation, the patient was treated for HCV and achieved an undetectable viral load. He was readmitted 6 months after transplant with a spontaneous perisplenic hematoma, weight loss, failure to thrive, low-grade fevers, and abnormal liver function tests. He had a rapid clinical deterioration and expired shortly after admission. His liver biopsy demonstrated EBV-negative monomorphic B-cell PTLD. Our case is the first to report an aggressive early-onset EBV-negative monomorphic B-cell PTLD in a HCV D+/R- liver transplant. This case illustrates the paucity of knowledge on HCV seroconversion and its involvement in EBV-negative monomorphic B-cell PTLD development.

Administration of Antithymocyte Globulin (Rabbit) to Treat a Severe, Mixed Rejection Episode in a Pregnant Renal Transplant Recipient.

Pregnancy in solid organ transplant recipients carries numerous risks to the mother such as increased risk of rejection, gestational diabetes mellitus, and preeclampsia. The developing fetus is subjected to risks such as birth defects, preterm delivery, and low birth weight. Typically, these risks can be managed through intensive, multidisciplinary prenatal care and a proper immunosuppressive regimen. In the setting of rejection, however, little data are available to suggest safe and effective treatment of acute cellular rejection, antibody-mediated rejection, or mixed rejection episodes in the pregnant solid organ transplant recipient. We describe the first case, to our knowledge, in which antithymocyte globulin (rabbit) was used to successfully treat a pregnant renal transplant recipient who experienced a mixed rejection episode. A 22-year-old, African American woman with stage 6 chronic kidney disease received a deceased donor renal transplant after undergoing hemodialysis for 3 years. Her maintenance immunosuppressive regimen at the time of transplantation consisted of tacrolimus, prednisone, and mycophenolate mofetil. Despite counseling efforts on the importance of having a planned pregnancy after kidney transplantation so that her immunosuppressive medications could be optimized, the patient became pregnant 12 months later; her mycophenolate mofetil was changed to azathioprine to reduce the risk of fetal deformities or death. Three months later, the patient was admitted for biopsy of her transplanted kidney and was evaluated for possible kidney rejection. After confirmation of a mixed 1B acute cellular rejection and antibody-mediated rejection episode, the patient decided to pursue resolution of her rejection episode and continue the pregnancy despite the potential risks to the fetus. She was treated with high-dose corticosteroids, intravenous immunoglobulin, plasmapheresis, and antithymocyte globulin (rabbit). Twenty-nine months after transplantation, the patient was induced and gave birth to a healthy baby boy. Our patient's case offers unique insight into the potential management of a rejection episode requiring aggressive immunosuppressive therapy. Although potent immunosuppressive therapies were successfully used in our patient, further studies are needed to make definitive recommendations regarding the use of such therapies for treatment of rejection episodes in pregnant solid organ transplant recipients. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made.