Heart-liver Transplantation Research Articles

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients

In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation. The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection. Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained. A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody=77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at<2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48months (interquartile range: 25 to 68months). There was 1 death due to metastatic cancer and no significant graft dysfunction. A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

Changes in multiorgan heart transplants following the 2018 allocation policy change.

This study evaluated the impact of the heart allocation policy change in 2018 on the characteristics and outcomes of multiorgan transplants involving heart allografts. Adults undergoing multiorgan heart transplantation from 2010 to 2020 were identified from the United Network for Organ Sharing (UNOS) registry. Transplants were stratified into occurring before versus after the October 2018 heart allocation change. The primary outcome was 1-year survival following transplantation. A Cox proportional hazards model was used to evaluate the risk-adjusted effect of the allocation policy change on outcomes between cohorts. A total of 1832 patients underwent multiorgan heart transplantation during the study period with 245 (13.37%) undergoing heart-lung transplantation, 244 (13.32%) undergoing heart-liver transplantation, and 1343 (73.31%) undergoing heart-kidney transplantation. There was a higher utilization of temporary MCSDs as well as longer ischemic times for all three types of transplantation following the policy change. Heart-lung and heart-liver recipients had a similar 1-year survival before and after the policy change (each p > .05). Renal failure requiring dialysis (29.5% vs. 39.4%, p = .001) as well as 1-year survival (88% vs. 82%; log-rank p = .01) were worse in the heart-kidney cohort after the organ allocation system modification. This study demonstrates similar trends in multiorgan transplants as has been observed in isolated heart transplants following the allocation change, including more frequent utilization of temporary mechanical support and longer ischemic times. Although outcomes have remained comparable in the new allocation era with heart-lung and heart-liver transplants, heart-kidney recipients have a worse 1-year survival following the change.

Immunosuppression considerations in simultaneous organ transplant.

Solid organ transplantation is a life-saving procedure for patients in the end stage of heart, lung, kidney, and liver failure. For patients with more than one failing organ, simultaneous organ transplantation has emerged as a viable treatment option. Immunosuppression strategies and outcomes for simultaneous organ transplant recipients have been reported, but often involve limited populations. Transplanting dual organs poses challenges in terms of balancing immunosuppression with immunologic risk and allograft damage from surgical complications. Furthermore, transplanting certain organs can impose considerations on the management of immunosuppression. For example, liver allografts may confer immunologic privilege and lower rates of rejection of other allografts. This review article evaluates immunosuppression strategies for simultaneous kidney-pancreas, liver-kidney, heart-kidney, heart-liver, heart-lung, lung-liver, and lung-kidney transplants. To date, no comprehensive review exists to address immunosuppressive strategies in simultaneous organ transplant populations. Our review summarizes the available literature and provides evidence-based recommendations regarding immunosuppression strategies in simultaneous organ transplant recipients.

Comparison of combined heart‒liver vs heart-only transplantation in pediatric and young adult Fontan recipients

Indications for a heart‒liver transplantation (HLT) for Fontan recipients are not well defined. We compared listing characteristics, post-operative complications, and post-transplant outcomes of Fontan recipients who underwent HLT with those of patients who underwent heart-only transplantation (HT). We hypothesized that patients who underwent HLT have increased post-operative complications but superior survival outcomes compared with patients who underwent HT. We performed a retrospective review of Fontan recipients who underwent HLT or HT at a single institution. Characteristics at the time of listing, including the extent of liver disease determined by laboratory, imaging, and biopsy data, were compared. Post-operative complications were assessed, and the Kaplan‒Meier survival method was used to compare post-transplant survival. Univariate regression analyses were performed to identify the risk factors for increased mortality and morbidity among patients who underwent HT. A total of 47 patients (9 for HLT, 38 for HT) were included. Patients who underwent HLT were older, were more likely to be on dual inotrope therapy, and had evidence of worse liver disease. Whereas ischemic time was longer for the group who underwent HLT, post-operative complications were similar. Over a median post-transplant follow-up of 17 (interquartile range: 5-52) months, overall mortality for the cohort was 17%; only 1 patient who underwent HLT died (11%) vs 7 patients who underwent HT (18%) (p = 0.64). Among patients who underwent HT, cirrhosis on pre-transplant imaging was associated with worse outcomes. Despite greater inotrope need and more severe liver disease at the time of listing, Fontan recipients undergoing HLT have post-transplant outcomes comparable with those of patients undergoing HT. HLT may offer a survival benefit for Fontan recipients with liver disease.

Part 2: Disease of the Heart and Liver: A Relationship That Cuts Both Ways.

Diseases known to affect both the heart and liver include a variety of infectious, autoimmune, and metabolic disorders, as well as toxins: most commonly alcohol. As damage to both the heart and liver progresses, transplantation is a reasonable therapeutic option. Heart failure patients with underlying congestive hepatopathy receiving cardiac transplant have demonstrated improved liver enzyme levels posttransplant. Patients with severe end-stage liver disease requiring a liver transplant must undergo careful preoperative evaluation as surgical stress exposes the myocardium to high levels of catecholamines. Clinicians must consider both cardiac and hepatic complications when evaluating heart failure, cirrhosis, and nonalcoholic fatty liver disease. In Part 2 of this review, we discuss new noninvasive techniques for assessing liver fibrosis in the preoperative stage. Both serum and radiologic studies, such as transient elastography, have begun to take the place of liver biopsy due to their decreased morbidity. Last, we explore the current research examining the benefit of combined heart-liver transplant, although more longitudinal outcome studies are needed.

Advances in Treatment of ATTRv Amyloidosis: State of the Art and Future Prospects.

Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy is a progressive disease that is transmitted as an autosomal dominant trait and characterized by multiple organ failure, including axonal sensory-motor neuropathy, cardiac involvement, and autonomic dysfunction. Liver transplantation (LT) and combined heart–liver transplantation, introduced in the 1990s, have been the only therapies for almost two decades. In 2011, tafamidis meglumine became the first specific drug approved by regulatory agencies, since then the attention toward this disease has progressively increased and several drugs with different mechanisms of action are now available. This review describes the drugs already on the market, those that have shown interesting results although not yet approved, and those currently being tested.

Abstract 16533: Heterogeneity of Fibrosis in Patients Undergoing Combined Heart-Liver Transplant

Introduction: Combined heart-liver transplant (CHLT) is indicated for patients with end-stage heart failure and concomitant irreversible liver injury. Given that liver dysfunction from congestive hepatopathy is common in patients with end-stage heart failure, it can be difficult to determine reversible from irreversible liver injury. Transjugular liver biopsy (TJLB) is frequently used to evaluate the severity of parenchymal injury, but is limited by heterogeneity of fibrosis across biopsy specimens. We sought to compare the fibrosis evaluation of the TJLB specimens as compared to the pathology of the liver explant at the time of CHLT. Methods: All CHLT cases at CSMC between 2007 and 2017 were included. Demographic and liver ultrasound (US) or abdominal computed tomography (CT) imaging was retrieved by chart review. TJLB was performed prior to transplant to determine the severity of liver fibrosis and was compared to the pathology of the liver explant. A biopsy was considered to show heterogenous fibrosis if there was at least a 2 stage difference between the predominant and secondary patterns. Results: Thirteen CHLTs were performed at our center during the study period. The median follow-up was 59 months (IQR 48-67). Mean age at transplant was 53 years (SD +/- 14.9) and 77% of patients were male. Indications for CHLT included cardiac cirrhosis (7), amyloidosis (2), HCV cirrhosis (2), and congenital heart disease (2). By imaging, 3/7 patients (43%) had US and CT evidence, 2/7 (29%) had US or CT evidence, and 2/7 (29%) had no evidence of liver nodularity US or CT. All patients diagnosed with cardiac cirrhosis had both TJLB and explant pathology for review. All TJLBs were graded as stage 4 fibrosis. Fibrosis on analysis of the liver explant was variable: stage 4 (2), stage 3-4 (3), stage 2-4 (1), and stage 1-4 (1). Thus, 2/7 patients (29%) showed heterogeneity of fibrosis in their explant as compared to their TJLB. Conclusions: We found heterogeneity of fibrosis in liver explants of patients that had stage 4 fibrosis (cirrhosis) by TJLB and underwent CHLT. Further work is needed to identify which heart transplant candidates will most benefit from CHLT.

Combined Sequential Heart-Liver Transplantation

Many single ventricle patients palliated with the Fontan operation suffer from Fontan failure and progressive liver disease. Combined heart-liver transplantation is a rarely utilized and complex transplant strategy available for select Fontan patients. At the Hospital of the University of Pennsylvania, all Fontan patients deemed eligible for a heart transplantation undergo a combined sequential dual organ transplantation with same-donor organs. This article describes the techniques utilized as well as current results.

Acute kidney injury and chronic kidney disease after combined heart-liver transplant in patients with congenital heart disease: A retrospective case series.

Although it is known that children undergoing heart transplantation are at increased risk for both AKI and CKD, renal function following CHLT remains understudied. All pediatric CHLT patients from 2006 to 2019 were included. The prevalence of AKI in the first 7 post-operative days, renal recovery at 30 post-operative days, and CKD were ascertained. AKI was defined as an increase in creatinine greater than 1.5 times baseline, and CKD, as an eCrCl less than 90mL/min/1.73m2 . The need for RRT was also analyzed. 10 patients were included, with an average age of 20years and an average listing time of 130days. Preoperatively, the median eCrCl was 91.12mL/min/m2 (IQR 70.51, 127.75min/mL/m2 ). 5 (50%) patients had CKD, with 4 at stage 2 and 1 at stage 3. AKI occurred post-operatively in 3 of 9 (33%) patients: 2 at stage 1 and 1 at stage 2. 2 (67%) resolved by 7days. Of the 5 patients who reached their 1-year follow-up, 1 (20%) had stage 3 CKD. Among 2 patients, neither had CKD at 5years. One patient required RRT 2weeks after CHLT. Despite an increased prevalence of preoperative CKD, patients undergoing CHLT have a lower AKI prevalence than those receiving an isolated heart or liver transplant. Of those with AKI, early renal recovery is common, although at 1year CKD remains present in 20%. Among long-term survivors, normal renal function is achievable.

Ethical decision-making in simultaneous heart-liver transplantation.

Simultaneous heart-liver (SHL) transplants are only a small proportion of overall heart and liver transplantation, they have been increasing in frequency and thus challenge the equitable allocation of organs. The incidence of SHL transplants is reviewed along with the outcomes of SHL transplants and their impact on the waitlist, particularly in the context of solitary heart and liver transplantation. The ethical implications, most importantly the principles of utility and equity, of SHL transplant are addressed. In the context of utility, the distinction of a transplant being life-saving versus life-enhancing is investigated. The risk of hepatic decompensation for those awaiting both solitary and combined organ transplantation is an important consideration for the principle of equity. Lastly, the lack of standardization of programmatic approaches to SHL transplant candidates, the national approach to allocation, and the criteria by which programs are evaluated are reviewed. As with all multiorgan transplantation, SHL transplantation raises ethical issues of utility and equity. Given the unique patient population, good outcomes, lack of alternatives, and overall small numbers, we feel there is continued ethical justification for SHL, but a more standardized nationwide approach to the evaluation, listing, and allocation of organs is warranted.

Research priorities in Fontan-associated liver disease.

Fontan-associated liver disease (FALD) is an emerging condition in patients who have undergone surgical correction of univentricular congenital heart disease. There is little known about the epidemiology of FALD, including risk factors for end-organ failure or hepatocellular carcinoma nor a consensus on surveillance guidelines. Furthermore, there is a need to understand the role of heart versus combined heart-liver transplantation in this population. Research is limited by systemic barriers hindering the ability to track longitudinal FALD outcomes. Nearly all patients post-Fontan develop histological features of FALD as a function of time post-Fontan, regardless of Fontan hemodynamics. In cases of end-organ disease, single-center studies have shown promising outcomes of combined heart-liver transplant in this population, with decreased rates of acute rejection. However, despite the burden of disease, it is not currently possible to identify the population of patients with FALD using existing clinical databases and registries due to a lack of diagnostic codes. Strategies proposed to address barriers to understanding FALD include developing appropriate diagnostic and transplant-related codes for existing registries. Efforts should also be targeted at initiating prospective studies to understand recognized comorbidities related to Fontan physiology, guided by a team of multidisciplinary subspecialists.

En Bloc Combined Heart and Liver Transplantation for End-Stage Heart Failure

Combined heart-liver transplant (CHLTx) remains the only option for long-term survival in patients with end-stage heart and hepatic failure. To date, there are a limited number of transplant centers in the United States that have conducted a CHLTx. Between July of 2009 and December 2019, our group has performed the largest series (N = 20) of <i>en bloc</i> CHLTx to date. En block combined heart-liver transplantation offers both grafts the opportunity to minimize dysfunction with shorter ischemic time compared to sequential heart-liver transplant. This technique simplifies the surgery in patients with complex venous anatomy such as heterotaxy patients and can be performed in dextrocardia or levocardia patients, irrespective of the side of inferior vena cava or superior vena cava. We describe our indications and detailed en block technique for combined heart-liver with its midterm outcome.

Considerations and experience driving expansion of combined heart-liver transplantation.

Heart transplantation concomitant with a liver transplant may be warranted when end-stage heart failure results in irreversible liver failure. Previously reported outcomes have been excellent yet the specific immunoprotective role of the liver allograft is not known. We review the current literature about the immunologic benefit for combined heart and liver transplantation (CHLT). The total number of combined heart and liver transplants continues to increase and accounts for approximately 25 cases per year. Familial amyloid polyneuropathy with cardiac cirrhosis is the most common indication for CHLT while adult congenital heart disease (CHD) with associated cirrhosis is increasing in frequency. The majority of recent registry data suggest a statistically equivalent to modestly improved survival advantage for CHLT compared with isolated heart transplantation. Direct mechanisms accounting for this survival advantage are not proven, but combined heart and liver transplants experience lower rates of acute cardiac rejection and cardiac allograft vasculopathy (CAV). Combined heart and liver transplants remain a small percentage of the total heart transplants worldwide, but the majority of recent literature confirms the safety and viability of this option for patients with end-stage heart and liver disease. Equivalent to modestly improved survival outcomes, lower rates of acute cardiac rejection and CAV warrant further investigation into the liver allograft's immunoprotective effect on the transplanted heart. The key mechanisms of tolerogenicity have important implications for surgical technique and immunosuppression requirements. Future directions include development of criteria for heart-liver transplant candidacy and identification of equitable allocation protocols.

Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations.

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.

Anesthetic considerations for combined heart--liver transplantation in patients with Fontan-associated liver disease.

The success of the Fontan procedure has led to increased survival of patients born with certain congenital heart disease to the point that new sequlae, as a result of Fontan circulation, are being discovered. Included among these is Fontan-associated liver disease (FALD). The purpose of this review is to present available literature on the perioperative management of the combined heart--liver transplantation (CHLT) in patients with FALD. The perioperative management of a combined heart-liver transplant in a patient with Fontan circulation is complex. The patient is at risk for hemodynamic disturbances, significant blood loss, coagulopathies, and metabolic derangements. The maintenance of an appropriate transpulmonary pressure gradient is paramount to success. Postoperative management should be accomplished by a multidisciplinary care team. Limited series have demonstrated good outcomes in patients who have undergone CHLT. The perioperative management of CHLT in patients with FALD is complex and available literature is limited. Future studies are needed to further assess proper perioperative management of patients with FALD who undergo CHLT.

Big Data in Transplantation Practice-the Devil Is in the Detail-Fontan-associated Liver Disease.

As a result of the Fontan procedure, the prognosis of congenital single-ventricle heart disease has improved, with many affected children surviving into adulthood. However, the unanticipated consequences of chronic exposure to Fontan hemodynamics have revealed a new set of secondary noncardiac complications. Fontan-associated liver disease (FALD) is characterized by progressive hepatic fibrosis in nearly all patients post-Fontan, with the potential to develop cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. A lack of data regarding FALD-related prognosis makes consideration of indications for and timing of heart alone versus combined heart-liver transplantation challenging. A multidisciplinary group within the American Society for Transplantation analyzed several administrative datasets to study the epidemiology of FALD. This approach presented several obstacles, and efforts to characterize FALD were limited by a lack of Fontan- and FALD-specific diagnostic codes and an inability to follow individual patients through multiple health systems. Several ongoing Fontan registries were also reviewed but these do not adequately capture FALD-related variables. Such barriers highlight the need for large-scale data collection in patients post-Fontan to better understand and care for this complex population. This study emphasizes the challenges of studying emerging transplant-related diagnoses in existing datasets and the need for mechanisms to adapt registries to appropriately identify patients with rare or emerging conditions.

Characteristics and Outcomes of Patients Undergoing Combined Organ Transplantation (from the United Network for Organ Sharing)

Studies have shown that highly selected patients who underwent combined heart-kidney (HK) and heart-liver transplants (HLv) have short- and long-term outcomes comparable to those observed in primary heart transplantation (HT). Adults patients with stage D heart failure that underwent combined HK, HLv, and heart-lung (HL) were identified in the United Network for Organ Sharing registry from 1991 to 2016, with follow-up through March 2018. We conducted inverse probability of treatment weighting survival analysis of long-term survival stratified by type of combined organ transplant, accounting for donor, recipient, and operative characteristics. We identified 2,300 patients who underwent combined organ transplant (HK 1,257, HLv 212, HL 831). HL recipients were more likely white (77%), women (58%), with congenital heart disease (44.5%), and longer waiting list time (median 195 days). HK transplant increased significantly during the study period where as HL decreased significantly. Median survival was 12.2 years for HK (95% confidence intervals [CI] 10.8 to 12.8), 12 for HLv (95% CI 8.6 to 17.6) but significantly lower at 4.5 years for HL (95% CI 3.6 to 5.8). Combined HK and HLv transplantation rates are increasing and long-term survival is comparable to primary HT, unlike HL which is associated with decreasing trends and significantly lower survival.

Temporal Trends and Outcomes of Patients Undergoing Combined Organ Transplantation: Insights from the United Network for Organ Sharing (UNOS)

Studies have shown that highly selected patients undergoing combined heart-kidney (HK) and heart-liver transplants (HL) have short- and long-term outcomes comparable to those observed in primary heart transplantation (HT). Adults patients with stage D heart failure that underwent combined HK, HLv and heart-lung (HL) were identified in the United Network for Organ Sharing (UNOS) registry between 1991 and 2016, with follow-up through March 2018. We conducted inverse-probability weighted estimator (IPWE) survival analysis of long-term survival stratified by type of combined organ transplant, accounting for donor, recipient and operative characteristics. We identified 2300 patients who underwent combined organ transplant (HK: 1,257, HLv: 212, HL: 831). HL recipients were more likely white (77%), females (58%), with congenital heart disease (44.5%), and longer waiting list time (median 195 days). HK transplant increased significantly during the study period where as HL decreased significantly (Figure). Median survival was 12.2 years for HK (95% Confidence intervals [CI], 10.8-12.8), 12 for HLv (95% CI 8.6-17.6) but significantly lower at 4.5 years for HL (95% CI 3.6-5.8) (Figure). Combined HK and HLv transplantation rates are increasing and long-term survival is comparable to primary HT, unlike HL which is associated with decreasing trends and significantly lower survival.

Outcomes of Heart and Combined Heart-Liver Transplant in Pediatric Fontan Patients

While combined heart-liver transplant (HLT) is being performed for Fontan patients, outcomes and indications remain poorly defined. We compared listing characteristics and post-transplant outcomes of Fontan patients with HLT to those with heart-only transplant (HT). We retrospectively reviewed all Fontan patients undergoing HT or HLT at our institution between 2006-2019. Pre-transplant liver disease at the time of listing, as determined by laboratory and radiology data, and MELD-XI, Child Pugh, and VAST scores, were compared between groups. The Kaplan Meier survival method was used to compare post-transplant survival and freedom from rejection (ISHLT Grade 2R+ or pAMR2+). Forty-two patients (33 HT, 9 HLT) were included. HLT patients were older, more likely to be on dual-inotrope therapy, had worse Child Pugh and VAST scores, and were more likely to have varices, ascites, splenomegaly, and cirrhosis on imaging (Table 1). While not significant, HLT patients tended to be more sensitized, had higher total bilirubin and creatinine, and lower platelet count. Over a median post-transplant follow-up of 22 (5, 62) months, overall mortality for the entire cohort was 19%; only one HLT patient died (11%) versus 7 (21%) HT patients (p=0.58, Figure 1). None of the HLT patients experienced rejection, whereas 11 (33%) HT patients had rejection (p=0.06). Despite a greater inotrope need and more severe liver disease at time of listing, patients undergoing HLT have post-transplant outcomes that are comparable, if not better, than Fontan patients with HT. There appears to be a protective effect from rejection with HLT.

PRA is Not Associated with Rejection in Combined Heart and Liver Transplantation

Combined heart liver transplantation (CHLT) is relatively rare with approximately 250 cases from 1988-2018 nationally, but with rising numbers each year due to excellent survival. CHLT outcomes have potential immunological benefits compared to heart transplant alone. Liver allografts have long been observed to be more tolerant to HLA mismatch while showing some degree of immune protection in combined organ transplantation. A retrospective analysis from our center's experience of CHLT was performed. Outcomes of patients who had pre-transplant elevated panel reactive antibodies (PRA) >50-99% were compared to those with 0% and those with a low to moderate PRA (1-50%). The hypothesis was tested with the Fisher's exact test. Between 1997 and 2019, 37 patients underwent CHLT. The average age was 42.4 years +/- 10 with 8 deaths (21.6%) ranging from day 2 to 4.5 years post-transplant (5, 13.5% within the first year). None of the deaths were due to rejection or primary graft dysfunction. There were no episodes of humoral rejection and there were 2 episodes (5.4%) of cellular rejection in hearts and 4 (10.8%) in livers (of these, one episode was dual organ rejection). There was no statistical significance at baseline between PRA and history of Fontan physiology, protein losing enteropathy, prior sternotomy, diabetes, hypertension or renal disease. Furthermore, there was no correlation between PRA and death, rejection of either organ, presence of donor specific antibodies, ejection fraction below 50% (1 month and 1 year), length of stay over 30 days, post-transplant hypertension, diabetes or renal disease (table 1). The degree of allosensitization was not associated with worse outcomes in the CHLT population. While the sample is small, it is a reassuring finding that may change the perception of risk when planning a CHLT in a highly sensitized patient.