Elevated AT1R Antibody and Morbidity in Patients Bridged to Heart Transplant Using Continuous Flow Left Ventricular Assist Devices.

BACKGROUND: We studied longitudinal levels of angiotensin-II type 1 receptor antibody (AT1R-Ab) and their effects on adverse events (death, treated rejection and cardiac allograft vasculopathy) in patients who were bridged to heart transplant using a continuous flow left ventricular assist device (LVAD). METHODS AND RESULTS: Sera of 77 patients bridged to heart transplant (from 2009 to 2017) were tested for AT1R-Ab and CRP before and after LVAD. Elevated AT1R-Ab was defined as >10.0 U/mL. The median follow-up after transplant was 3.6 years (interquartile range, 2.2-5.6 years). After LVAD, AT1R-Ab levels increased from baseline and remained elevated until transplant. Freedom from adverse events at 5 years was lower in those with elevated AT1R-Ab levels at time of transplant. In an adjusted, multivariable Cox analysis, an AT1R-Ab level of >10 U/mL was associated with developing the primary end point (adjusted hazard ratio 3.4, 95% confidence interval 1.2-9.2, P = .017). Although C-reactive protein levels were high before and after LVAD placement, C-reactive protein did not correlate with AT1R-Ab. CONCLUSIONS: In LVAD patients bridged to heart transplant, an increased AT1R-Ab level at time of transplant was associated with poor outcomes after heart transplant. Post-LVAD AT1R-Ab elevations were not correlated with serum markers of systemic inflammation. Larger studies are needed to examine the pathologic role of AT1R-Ab in heart transplant.

Circulating angiotensin type II receptor: Possible marker for antibody mediated rejection after renal transplantation?

BACKGROUND: Presence of antibody [Ab] against angiotensin receptor [AT1R] indicates heightened risk for antibody mediated rejection [AMR] after transplantation but is insufficient as a marker. We speculated AT1R might be released systemically because of AMR and might be a useful biomarker. METHODS: AT1R was measured in blood from 73 Normals and 72 renal patients pre- and post-transplantation. Patients were stratified as AMR-free [Gp1], AMR<1yr [Gp2] and AMR>1yr [Gp3]. RESULTS: AT1R was higher [13±26vs.367±537, p<0.01)] and more prevalent [20% vs. 92%, p<0.01] among renal patients than Normals. Pretransplant levels were similar [p=ns] between groups. One-year posttransplant levels approached [p<0.01] normalcy for Gps1+3 but spiked during AMR and remained elevated [155±58, p<0.01] for 50% Gp2 patients. One-year AT1R levels were higher among subsequent graft failures than surviving grafts [171±267vs. 38±50, p<0.01]. CONCLUSIONS: Pretransplant AT1R was abnormally elevated: possibly indicating ongoing tissue injury. Pretransplant AT1R didn't predict risk for AMR. However, AT1R spiked during early AMR and sustained elevations were associated with poorer outcomes.

Perioperative Desensitization Improves Outcomes Among Crossmatch Positive Recipients of Deceased Donor Renal Transplants.

CONTEXT: Graft failure due to chronic rejection is greater among renal transplant patients with donor-specific antibody (DSA) than among DSA-free patients. For patients dependent on deceased donor transplantation, preoperative desensitization to eliminate DSAs may be impractical. We speculated that perioperative desensitization might eliminate preexisting DSAs and prevent de novo DSAs and improve graft outcomes. We report that brief perioperative desensitization using either intravenous immunoglobulin (IVIG) or plasmapheresis/IVIG (PP/IVIG) treatment improves clinical outcomes among patients with positive crossmatches. DESIGN: Immediately following deceased donor transplantation, 235 renal recipients were assigned points for PRA and flow crossmatches (FCXM): delayed graft function (DGF) ≤ 1 point received standard therapy; 2 points received high-dose IVIG; and ≥3 points received PP/IVIG. The DSAs were serially monitored by single antigen bead luminex for 1 year. Five-year clinical outcomes were determined from the chart review. RESULTS: All desensitized patients had preoperatively positive FCXM with DSA. Rejection was more common (P < .05) among desensitized than nonsensitized groups. However, overall graft survivals were similar between the groups (P = not significant) and superior to historic untreated patients (P < .05). Treatment with PP/IVIG more effectively eliminated preexisting DSAs (67% vs 33%, P < 0.05) than IVIG, but neither regimen prevented de novo formation of DSA (20%, P = not significant). Graft survival was >90% in all desensitizated patients with DSA elimination as well as PP/IVIG patients with residual DSA. In contrast, IVIG patients with persistent DSA had poorer graft survival (45%, P < .05). CONCLUSION: Preemptive perioperative desensitization improved overall graft survival of sensitized patients compared to historic untreated patients. Plasmapheresis/IVIG had greater impact on DSA eradication and graft survival than IVIG alone.

Post-transplant Desensitization for Deceased Donor Kidney Transplant Recipients: A Single Center Experience.

The highly-sensitized kidney transplant candidate with no available living donors remains at a major disadvantage with decreased access and worse outcomes post-transplant. We have previously reported our initial data on both pre-transplant and post-transplant desensitization. We observed only a modest decline in unacceptable antigens with pretransplant intravenous immunoglobin (IVIG) and rituximab. Due to these observations, we have focused on a peri-operative post-transplant desensitization protocol in our program. Beginning in 2006, we implemented a simple point-based algorithm [variables included: panel reactive antibody (PRA) status; flow cytometric crossmatch (FCXM); and delayed graft function] to identify kidney transplant recipients who would undergo peri-operative plasmapheresis/IVIG to abrogate preformed antibody-mediated allograft rejection (AMR). Our previous results suggested acceptable 5-year outcomes. Here, in an expanded population (N=66), we report an overall death-censored graft survival of 73% at a mean follow-up of 8.5 years post-transplant. Our patients were largely African American (85%) and regrafts (39%), with a median PRA of 88%, and a mean T- and B-FCXM of 97 mean channel shifts (MCS) and 117 MCS, respectively. Although acute AMR rates were acceptable (12%), 22% of patients developed chronic AMR. A pre-transplant T-cell FCXM of > 200 MCS (p=0.02) or presence of donor specific antibodies (DSA) at most recent follow-up (p=0.02) were associated with graft loss. Current studies with revised protocols utilizing additional DSA information, surveillance biopsies, and proteasome inhibition are ongoing.

Effects of Two Preemptive Post-transplant Desensitization Regimens Upon Renal Allograft Survival and DSA Elaboration.

We used a simple point-based algorithm to identify patients who might benefit from desensitization because of their higher risk of antibody-mediated chronic rejection and graft failure. Points were assigned to known but easily determined risk factors (panel reactive antibody, flow crossmatch, delayed graft function) and calculated immediately after deceased donor kidney transplantation. Point totals were used to identify: 1) which patients would receive desensitization; and, 2) which regimen each patient would receive. This standardized approached resulted in improved overall graft survival in both modalities compared to historically untreated sensitized patients. While preemptive desensitization positively impacted clinical metrics, the improvements were unequal between regimens. PP/IVIG treatment clearly resulted in greater elimination of preexisting donor specific antibodies against HLA antigens (DSA), fewer late rejections, and superior 3-year graft survival among patients who resolved their DSA as well as those with persistent DSA. Since graft survival among PP/IVIG recipients was excellent even when preexisting DSA were still present one year post-transplant, it suggests that the benefit of this regimen is two-fold: first to increase DSA elimination among patients, and secondly, to minimize downstream immune activating events such as rejection. In contrast, IVIG patients with persistent DSA had more rejections and graft survival only slightly better than if they had no treatment at all. Since the IVIG group also had a preponderance of Class II directed DSA, we cannot discount the influence of that specificity upon graft outcomes. Additional studies are needed to confirm our findings and to allow more effective assessment of the impact of DSA specificity upon desensitization efficacy and graft success.

Graft-versus-host disease after solid organ transplantation: a single center experience and review of literature.

BACKGROUND: Graft-versus-host disease (GVHD) is an uncommon cause of morbidity and mortality after solid organ transplantation that is most likely under-diagnosed. We describe our single center experience with three cases of GVHD diagnosed over a period of 15 years in a total of 2,271 solid organ transplant recipients. CASE REPORTS: We describe three case reports: (1) a 3-week old neonate who developed GVHD 16 months after living-related liver transplant, (2) a 14-year old adolescent who developed GVHD 4 months following an unrelated cadaveric pancreas transplant and; (3) a 27-year old male who developed GVHD 18 days after simultaneous kidney-pancreas transplant from an unrelated donor. GVHD was confirmed through skin biopsies, engraftment profile from bone marrow biopsy and variable number tandem repeat analysis. Treatment strategies included use of corticosteroids and sirolimus monotherapy, corticosteroids and mesenchymal stromal cell therapy and reduction of immunosuppression. We observed that African-American race, sexual and HLA mismatching and cytomegalovirus infection may be high risk factors for development of GVHD following solid organ transplant. CONCLUSIONS: GVHD continues to be a rare but fatal complication following solid organ transplantation that demands a high index of clinical suspicion for diagnosis and management. Future approaches may focus on early recognition of risk factors and improving treatment protocols using a combination of mesenchymal stromal cell transplantation with pharmacotherapy.

Surveillance of alloantibodies after transplantation identifies the risk of chronic rejection.

The monitoring of the levels of alloantibodies following transplantation might facilitate early diagnosis of chronic rejection (CR), the leading cause of renal allograft failure. Here, we used serial alloantibody surveillance to monitor patients with preoperative positive flow cytometric crossmatch (FCXM). Sixty-nine of 308 renal transplant patients in our center had preoperative positive FCXM. Blood was collected quarterly during the first postoperative year and tested by FCXM and single antigen bead luminometry, more sensitive techniques than complement-dependent cytotoxic crossmatching. Distinct post-transplant profiles emerged and were associated with different clinical outcomes. Two-thirds of patients showed complete elimination of FCXM and solid-phase assay reactions within 1 year, had few adverse events, and a 95% 3-year graft survival. In contrast, the remaining third failed to eliminate flow FCXM or solid-phase reactions directed against HLA class I or II antibodies. The inferior graft survival (67%) with loss in this latter group was primarily due to CR. Thus, systematic assessment of longitudinal changes in alloantibody levels, either by FCXM or solid-phase assay, can help identify patients at greater risk of developing CR.

A novel post-transplant alloantibody surveillance and intervention strategy that improves graft outcomes in sensitized renal transplant recipients.

Chronic rejection, the leading cause of renal graft failure, is mediated by alloantibody graft destruction. Monitoring alloantibodies posttransplant might facilitate early diagnosis of alloantibody mediated graft destruction and provide an opportunity for intervention. Herein, we describe our alloantibody surveillance and intervention protocol that has improved graft survival. Patients (n = 69) with preoperatively positive FCXM and DSA were transplanted. Patient compatibility with donors was assessed by FCXM and donor specific antibody using single antigen bead Luminex. FCXM and DSA levels were monitored quarterly posttransplant. We identified a posttransplant profile strongly associated with chronic rejection. We then implemented a point-based formula that indicated when to initiate preemptive treatment with IVIG and plasmapheresis. The results of posttransplant antibody surveillance revealed 2 profiles. Most patients (65%) showed complete elimination of FCXM reactivity and DSA levels within 12 months of transplant. Three-year graft survival exceeded 95% and patients were chronic rejection-free. In contrast, the remaining patients failed to eliminate antibody as assessed by FCXM and DSA levels. Graft survival was inferior and chronic rejection was diagnosed in 43% of the group. Subsequent inclusion of preemptive treatment using the point-based system improved 3-year graft survival from 50% to 90%. In conclusion, the data show that implementation of an evidence based antibody surveillance protocol and an intervention protocol successfully improved graft survival.

Quantitation of alloantibody concentration can predict patient sensitivity to intravenous immunoglobulin desensitization.

Despite the success of intravenous immunoglobulin (IVIg) desensitization to reduce anti-human leukocyte antigen antibodies, its high failure rate and expense limit its usefulness. We speculated that quantitation of alloantibody concentration could allow early identification of IVIg resistant patients. Patients were described as nonresponders (n=3) or responders (n=8). Panel reactive antibodies (PRA) were determined using Flowbeads and concentration calculated as molecules of equivalent soluble fluorochrome (MESF). PRA was equivalent between nonresponders and responders before (97+/-3% vs. 76+/-20%, P=NS) and after 3 IVIg/plasmapheresis (PP) treatments but lower among responders at end-of-treatment (76+/-20% vs. 44+/-15%, P<0.01). In contrast, pretreatment MESFs were higher (333,640+/-241,352 vs. 38,741+/-5,133, P=0.006) among nonresponders than responders. During treatment, MESFs decreased (P<0.05) in 0 of 3 nonresponders vs. 8 of 8 responders. Final MESFs were higher among nonresponders than responders. We report that quantitation of MESFs allows early identification of IVIg/PP resistant patients. This sensitive and inexpensive technique should allow more effective patient selection and reduce the costs associated with desensitization.

Living donor liver transplant with clinical tolerance, laboratory evidence of chimerism, and spontaneous clearance of HBV.

We present a case of functional and histopathologic tolerance, chimerism, and spontaneous clearance of HBV in a patient four years after living donor liver transplant (LDLT). A 19-year-old male patient underwent a LDLT for HBV cirrhosis. He voluntarily ceased immunosuppression and antiviral therapy after 6 months. He is now four years status post transplant without any episodes of rejection or clinical manifestation of liver disease. PCR and VNTR were used to show donor-recipient chimerism and a large degree of genetic similarity between the pair. MLC and cytokine elaboration were used to show recipient hyporeactivity towards donor antigen. He also has clinical evidence of clearing his HBV without continued use of HBIG.