Faculty Bibliography

Kidneys from donors with blood type A2 can be successfully transplanted into blood type B and O recipients without the need for desensitization if the recipient's starting anti-A hemagglutinin titer is within an acceptable range. National kidney allocation policy now offers priority for eligible B recipients to receive A2 or A2B deceased donor kidneys, and therefore, the frequency with which A2 or A2B to B transplants will occur is expected to increase. The precise mechanisms by which antibody-mediated rejection is averted in these cases despite the presence of both circulating anti-A antibody and expression of the A2 antigen on the graft endothelium are not known. Whether this process mirrors proposed mechanisms of accommodation, which can occur in recipients of ABO incompatible transplants, is also not known. Repeated exposure to mismatched antigens after retransplantation could elicit memory responses resulting in antibody rebound and accelerated antibody-mediated rejection. Whether this would occur in the setting of repeated A2 donor exposure was uncertain. Here we report the case of a patient with history of a prior A2 to B transplant which failed owing to nonimmunologic reasons; the patient successfully underwent a repeat A2 to B transplant. Neither rebound in anti-A2 antibody nor clinical evidence of antibody-mediated rejection were observed after the transplant. Current kidney allocation will likely enable more such transplants in the future, and this may provide a unique patient population in whom the molecular mechanisms of incompatible graft accommodation may be investigated.

OBJECTIVES/OBJECTIVE:The presence of a donor-specific positive crossmatch has been considered to be a contraindication to kidney transplantation because of the risk of hyperacute rejection. Desensitization is the process of removing hazardous preformed donor-specific antibody (DSA) in order to safely proceed with transplant. Traditionally, this involves plasmapheresis and intravenous immune globulin treatments that occur over days to weeks, and has been feasible when there is a living donor and the date of the transplant is known, allowing time for pre-emptive treatments. For sensitized patients without a living donor, transplantation has been historically difficult. SUMMARY OF BACKGROUND DATA/BACKGROUND:IdeS (imlifidase) is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG. METHODS:Here we present our single-center's experience with 7 highly sensitized (cPRA98-100%) kidney transplant candidates who had DSA resulting in positive crossmatches with their donors (5 deceased, 2 living) who received IdeS within 24 hours prior to transplant. RESULTS:All pre-IdeS crossmatches were positive and would have been prohibitive for transplantation. All crossmatches became negative post-IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and antibody-mediated rejection, which responded to standard of care therapies. Three patients had delayed graft function, which ultimately resolved. No serious adverse events were associated with IdeS. All patients have functioning renal allografts at a median follow-up of 235 days. CONCLUSION/CONCLUSIONS:IdeS may represent a groundbreaking new method of desensitization for patients who otherwise might have no hope for receiving a lifesaving transplant.

Kidney transplant recipients (KTR) have greater morbidity and length of stay (LOS) following certain surgical procedures than non-KTR. Given that appendectomy is one of the most common surgical procedures, we investigated differences in outcomes between 1336 KTR and 2,640,247 non-KTR post-appendectomy at transplant and non-transplant centers in the US from 2000-2011, using NIS data and adjusting for patient and hospital level factors. Postoperative complications were identified using ICD9 codes. Among KTR, there were no post-appendectomy in-hospital deaths, compared to a 0.2% in non-KTR (p=0.5). Overall complications were similar among KTR and non-KTR (17.0% vs 11.6%; aOR:_0.771.12_1.61). LOS and costs were greater for KTR compared to non-KTR (LOS ratio_1.191.31_1.45; cost ratio_1.111.17_1.26). Only 44.8% of KTR had laparoscopic approach compared to 54.5% of non-KTR, but had similar complication rates (10.6 vs 8.7%, p 0.5). When treated at transplant centers, KTR had similar complications (aOR_0.440.79_1.43), but longer LOS (ratio_1.211.37_1.55) and greater hospital-associated costs (ratio_1.191.29_1.41) than non-KTR. Conversely, at non-transplant centers, KTR and non-KTR had similar complications (aOR_0.751.23_2.0), LOS (ratio_0.840.96_1.09), and cost (ratio_0.931.01_1.10). Contrary to other procedures, KTR did not constitute a high-risk group for patients undergoing appendectomy.

OBJECTIVE:To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and mortality. BACKGROUND:Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its effect on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including delayed graft function, early hospital readmission, immunosuppression intolerance, and mortality. METHODS:We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n = 74,859) and tested whether (1) frailty, measured immediately before KT in a novel cohort (n = 589), was associated with LOS (LOS: negative binomial regression; LOS ≥2 weeks: logistic regression) and (2) whether frailty modified the association between LOS and mortality (interaction term analysis). RESULTS:Frailty was independently associated with longer LOS [relative risk = 1.15, 95% confidence interval (CI): 1.03-1.29; P = 0.01] and LOS ≥2 weeks (odds ratio = 1.57, 95% CI: 1.06-2.33; P = 0.03) after accounting for registry-based risk factors, including delayed graft function. Frailty also attenuated the association between LOS and mortality (nonfrail hazard rate = 1.55 95% CI: 1.30-1.86; P < 0.001; frail hazard rate = 0.97, 95% CI: 0.79-1.19, P = 0.80; P for interaction = 0.001). CONCLUSIONS:Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical LOS.

Successful renal transplantation requires low-pressure venous drainage to permit adequate outflow from the allograft. We report here a series of three patients in whom the inferior vena cava as well as bilateral iliac veins were thrombosed, making it necessary to explore less traditional vessels for venous drainage of the renal allograft. We utilized the splanchnic vasculature in two cases, and the native left renal vein in another. The resulting atypical intra-abdominal locations of these allografts also presented difficulties for arterial anastomoses and for urinary drainage. Arterial conduits were utilized in two cases to facilitate anastomosis to the common iliac artery or the aorta and in the third case, the splenic artery was used for arterial inflow. A traditional ureterocystostomy was technically feasible for only one patient. In another, ureteroureterostomy to the native ureter was performed, and in the third case the creation of an ileal conduit was necessary. All three patients had antibodies to human leukocyte antigens and two required desensitization. All three kidneys had immediate graft function and continued to function at one year post-transplant. With a combination of planning, creativity, and persistence, patients with IVC thrombosis can enjoy the benefits of renal transplantation.

BACKGROUND Treatment with DAAs before deceased donor liver transplantation has been shown to be an effective strategy to prevent post-transplant HCV recurrence, with a 95% cure-rate among individuals who achieve undetectable HCV VL for >/=30 days pre- transplant. This strategy has not been evaluated in LDLT. MATERIAL AND METHODS We evaluated outcomes in LDLT recipients treated with DAAs pre-transplant and bridged with 4 weeks of post-transplant SOF. All cases of LDLT at Johns Hopkins (1/1/2014-3/1/15) were retrospectively reviewed. RESULTS There were 4 HCV+ LDLT cases treated with DAAs pre- and post-transplant. Pre-transplant DAA regimens included SOF plus SIM in 2 cases of HCC and SOF plus RBV in 2 cases of ESLD. All patients achieved negative VL by week 7 of treatment and all patients had at least 30 days of HCV RNA negativity at the time of LDLT. Patient 4 had a delay in LDLT due to uncontrolled pulmonary hypertension, and experienced viral breakthrough because of treatment interruption. Due to concerns for SOF resistance, a salvage regimen of LDV-SOF and SIM was used. Post-LDLT patients 1-3 received 4 weeks of SOF monotherapy and patient 4 received 14 weeks of LDV-SOF. Three patients achieved SVR12. One died from non-HCV related complications at 4 months post-LDLT. CONCLUSIONS Our preliminary experience suggests that bridging DAAs pre- and post-LDLT is an effective strategy to prevent HCV recurrence. With delays in transplant and prolonged use of SOF/RBV, there is a risk of viral breakthrough, but a salvage strategy of triple DAA therapy can be effective.

The required intensity of monitoring for antibody-mediated rejection (AMR) after of ABO-incompatible (ABOi) kidney transplantation is not clearly formulized. We retrospectively evaluated a single-center cohort of 115 ABO-incompatible (ABOi) kidney transplant recipients, of which 32% were also HLA-incompatible (ABOi/HLAi) with their donors. We used an adjusted negative binomial model to evaluate risk factors for late AMR. Using this model, we risk-stratified patients into high- and low-risk groups for the development of late AMR. 26% of patients had at least one AMR episode. 49% of AMR episodes occurred within 30-days after transplant and were considered early AMR. Patients with an early AMR episode had a 5.5-fold greater incidence of developing late AMR (IRR=5.5,[95%CI:1.5-19.3],p=0.01). ABOi/HLAi recipients trended towards increased late AMR risk (IRR=1.9,[95%CI:0.5-6.6],p=0.3). High-risk recipients (those with an early AMR or those who were ABOi/HLAi) had a 6-fold increased incidence of late AMR (IRR=6.3,[95%CI:1.6-24.6],p=0.008) versus low-risk recipients. The overall incidence of late AMR was 20.8% versus 1.5% in low-risk recipients. Changes in anti-A/B titer did not correlate with late AMR (IRR=0.9 per log titer increase, p=0.7). This risk-stratification scheme uses information available within 30-days of ABOi transplantation to determine risk for late AMR and can help direct longitudinal follow-up for individual patients

BACKGROUND:Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. METHODS:Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. RESULTS:Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poor: PR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk. CONCLUSIONS:Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.

BACKGROUND:Patients undergoing liver transplantation frequently but inconsistently require massive blood transfusion. The ability to predict massive transfusion (MT) could reduce the impact on blood bank resources through customization of the blood order schedule. Current predictive models of MT for blood product utilization during liver transplantation are not generally applicable to individual institutions owing to variability in patient population, intraoperative management, and definitions of MT. Moreover, existing models may be limited by not incorporating cirrhosis stage or thromboelastography (TEG) parameters. METHODS:This retrospective cohort study included all patients who underwent deceased-donor liver transplantation at the Johns Hopkins Hospital between 2010 and 2014. We defined MT as intraoperative transfusion of > 10 units of packed red blood cells (pRBCs) and developed a multivariable predictive model of MT that incorporated cirrhosis stage and TEG parameters. The accuracy of the model was assessed with the goodness-of-fit test, receiver operating characteristic analysis, and bootstrap resampling. The distribution of correct patient classification was then determined as we varied the model threshold for classifying MT. Finally, the potential impact of these predictions on blood bank resources was examined. RESULTS:Two hundred three patients were included in the study. Sixty (29.6%) patients met the definition for MT and received a median (interquartile range) of 19.0 (14.0-27.0) pRBC units intraoperatively compared with 4.0 units (1.0-6.0) for those who did not satisfy the criterion for MT. The multivariable model for predicting MT included Model for End-stage Liver Disease score, whether simultaneous liver and kidney transplant was performed, cirrhosis stage, hemoglobin concentration, platelet concentration, and TEG R interval and angle. This model demonstrated good calibration (Hosmer-Lemeshow goodness-of-fit test P = .45) and good discrimination (c statistic: 0.835; 95% confidence interval, 0.781-0.888). A probability cutoff threshold of 0.25 was found to misclassify only 4 of 100 patients as unlikely to experience MT, with the majority such misclassifications within 4 units of the working definition for MT. For this threshold, a preoperative blood ordering schedule that allocated 6 units of pRBCs for those unlikely to experience MT and 15 for those who were likely to experience MT would prevent unnecessary crossmatching of 338 units/100 transplants. CONCLUSIONS:When clinical and laboratory parameters are included, a model predicting intraoperative MT in patients undergoing liver transplantation is sufficiently accurate that its predictions could guide the blood order schedule for individual patients based on institutional data, thereby reducing the impact on blood bank resources. Ongoing evaluation of model accuracy and transfusion practices is required to ensure continuing performance of the predictive model.