Kyle L. Dawson

Treatment of hyperacute antibody-mediated lung allograft rejection with eculizumab

We report the case of a highly sensitized (cPRA 99%, Class II) 56-year-old white female with a lung allocation score of 38, who underwent double lung transplantation for pulmonary fibrosis and pulmonary hypertension. Pre-transplant desensitization with multiple courses of plasma exchange (PE) and intravenous immunoglobulin (IVIg) was largely unsuccessful. The surgical operation was uneventful; however, the patient was found to have a positive prospective B-cell crossmatch according to both anti-human globulincomplement-dependent cytotoxicity and flow cytometry studies. At the time of transplant, the recipient had the following donor-specific antibodies (DSAs): DR8 (15,000 MFI); DR14 (14,000 MFI); DR52 (15,000 MFI); and DQ7 (3,800 MFI). PE was performed on post-operative days (PODs) 1, 0 and 1, and IVIg was given along with rituximab and bortezomib due to the positive B-cell crossmatch. Repeat DSAs post-implantation/PE were initially negative; however, the patient subsequently developed acute graft dysfunction (Figure 1) and, by POD 2, the P/F ratio had fallen from 106 to 33 and she was initiated on extracorporeal membrane oxygenation (ECMO), nitric oxide, multiple pressors and renal replacement therapy. An open-lung biopsy was performed showing neutrophilic capillaritis and C4d positivity suggestive of antibody-mediated rejection (AMR). An ensuing set of DSAs showed the antibodies against DR8, DR14, DR52 and DQ7 were again present. On POD 2, the decision was made to hold PE and give the anti-C5 antibody, eculizumab, which dramatically halted the disease progression. Extracorporeal membrane oxygenation (ECMO) was discontinued after 3 days and the chest X-ray gradually improved. After the initial 1,200-mg dose, 600 mg of eculizumab was again given on PODs 6, 8 and 9, for a cumulative dose of 3,000 mg, along with 4 doses of bortezomib 1.3 mg/m, 2 doses of rituximab 375 mg/m, 160 g of IVIg and 3 PEs post-transplant (Figure 2). After weaning off ventilator support and hemodialysis, the patient was discharged on POD 47. The 1-month biopsy was 15% positive for C4d, and the 3-month biopsy was unremarkable. The patient is now alive and well at 1 year post-transplant with no re-hospitalizations, infectious complications or

A new epoprostenol formulation for the treatment of pulmonary arterial hypertension

PURPOSE The pharmacology and pharmacokinetics of a novel formulation of epoprostenol for the treatment of pulmonary arterial hypertension (PAH) are reviewed, with guidance on addressing a number of important safety considerations. SUMMARY Epoprostenol is a direct vasodilator of the pulmonary and systemic vasculature indicated for improving exercise capacity in patients with PAH. Veletri, a recently approved formulation of epoprostenol for continuous i.v. infusion, offers increased stability relative to other available epoprostenol products. Therefore, the use of Veletri can lessen the therapy burden associated with the other available formulation of the drug by allowing for the advance preparation of infusion pump cassettes (at certain concentrations) and administration at room temperature without the need for cooling with ice packs. Sterility, however, is of concern with outpatient preparation of epoprostenol-containing cassettes stored for the maximum duration according to stability guidelines. All epoprostenol infusions are classified as high-risk therapies due to complex dosing, the drugs short half-life, and the potential for life-threatening rebound PAH with abrupt discontinuation. Adverse effects reported in ≥10% of participants in clinical trials of Veletri included flushing (58%), headache (49%), nausea or vomiting (32%), hypotension (16%), chest pain (11%), and anxiety, nervousness, or agitation (11%). As with other epoprostenol formulations, the use of Veletri requires an evaluation of health-system medication-use practices to ensure patient safety. CONCLUSION Veletri provides an epoprostenol therapy option that reduces some of the inconveniences of the other formulation. Drug stability is dependent on cassette concentrations, which may be limited by sterility concerns with outpatient preparation. Use of this new agent within the health system requires an evaluation of practices to ensure patient safety.

Effect of Hypogammaglobulinemia on the Incidence of Community-Acquired Respiratory Viral Infections After Lung Transplantation

BACKGROUND Hypogammaglobulinemia (HGG) has been associated with an increased risk of infectious complications in lung transplant recipients, but its effect specifically on community-acquired respiratory viruses (CARVs) remains unknown. This study aimed to determine if lung transplant recipients with HGG are at an increased risk of developing CARV infection. Secondary endpoints included the effect of HGG on lung function, incidence of rejection, and mortality. METHODS A retrospective review of all lung transplant recipients from 2008 to 2011 was performed. Patients were stratified as either having HGG after transplantation or having normal IgG titers according to their nadir IgG level. HGG was defined a serum IgG level of <700 mg/dL. CARVs included human metapneumovirus, influenza A/B, respiratory syncytial virus A/B, parainfluenza 1/2/3, rhinovirus, and adenovirus isolated from bronchoalveolar lavage/wash, sputum, or nasal swab. RESULTS The cohort consisted of 263 patients with a mean follow-up time of 612 ± 356 days. The incidence of CARV infection was 27% in patients with normal IgG titers and 23.4% in patients with HGG (P = .62). No difference in rejection, mortality, or lung function was found between the groups. As expected, patients who ever had a CARV infection had a significantly lower 1-second forced expiratory volume % reference on their most recent spirometry than those who had not had a CARV infection (81.6% vs 86.9%; P = .027). CONCLUSIONS Although CARV infection has been shown to affect lung graft function, these data suggests that HGG is not associated with the incidence of CARV infection.

Effect of immunosuppression for first kidney or kidney/pancreas transplant on sensitization at the time of second transplant.

Background. Previously transplanted patients are more likely to be sensitized, leading to prolonged waitlist times and decreased graft survival. This analysis of the United Network for Organ Sharing kidney/pancreas transplant database investigates factors at the time of first transplant associated with increased sensitization in patients undergoing second transplantation. Methods. Records of nonsensitized patients (panel reactive antibodies [PRA] <20%) receiving a primary transplant in 1999 or later were analyzed to determine whether immunosuppressive agents at the time of first transplant were associated with a change in PRA from first to second transplant. Variables included gender, race, human leukocyte antigen (HLA) mismatch, rabbit antithymocyte globulin (RATG), interleukin-2 receptor antagonists, tacrolimus (FK), cyclosporine A (CSA), and mycophenolate mofetil/sodium (MMF). Results. For the primary endpoint of increase in PRA greater than or equal to 20%, African Americans (AA) versus non-AA (OR 2.63, P<0.0001) and HLA nonzero mismatch versus zero mismatch (OR 2.90, P<0.0001) were associated with increased sensitization. The effect of immunosuppressive regimen depended on race and HLA status. In non-AAs/HLA mismatch (1–6), interleukin-2 receptor antagonists versus RATG (OR 1.40, P=0.001), CSA versus FK (OR 1.69, P<0.001) and no MMF versus MMF (OR 1.39, P<0.001) were also associated with increased sensitization. In AAs/HLA mismatch (1–6), no induction versus RATG (OR 1.59, P=0.031) and CSA versus FK (OR 1.68, P=0.006) were associated with increased sensitization. Conclusions. These data suggest a reduced risk of sensitization at the time of second transplant when using more potent immunosuppression with RATG, FK, and MMF for nonsensitized primary kidney or kidney/pancreas transplant patients. These effects seem to be related to race and HLA mismatch.

Effects of Rituximab on the Development of Viral and Fungal Infections in Renal Transplant Recipients

Background. Rituximab is becoming increasingly utilized in renal transplant recipients; however, its association with infections remains unclear. Methods. We reviewed the incidence of viral and fungal infections in kidney transplant recipients treated with () or without () rituximab (RTX) in addition to standard immunosuppression. Results. Infections occurred in 134 (30%) patients, with a greater proportion in RTX versus no RTX patients (47% versus 28%; ). Viral infections occurred in 44% and 27% of RTX and no RTX patients, respectively (). This was largely driven by the frequency of BK viremia and noncytomegalovirus/non-BK viruses in RTX patients (27% versus 13% () and 15% versus 2% (), resp.). Fungal infections also occurred more often in RTX patients (11% versus 3 %; ). Multivariate analysis revealed deceased donor recipient (odds ratio = 2.5; ) and rituximab exposure (odds ratio = 2.2; ) as independent risk factors for infection. Older patients, deceased donor recipients, those on dialysis longer, and those with delayed graft function tended to be at a greater risk for infections following rituximab. Conclusions. Rituximab is associated with an increased incidence of viral and fungal infections in kidney transplantation. Additional preventative measures and/or monitoring infectious complications may be warranted in those receiving rituximab.

Cardioprotective medication use after renal transplantation

Dawson KL, Patel SJ, Putney D, Suki WN, Gaber AO. Cardioprotective medication use after renal transplantation. 
Clin Transplant 2010: 24: E253–E256.

Clostridium difficile infection after lung transplantation: Are we really doing everything possible?

Clostridium difficile infection (CDI) is now the leading cause of healthcare-associated diarrhea in the hospitalized population (1% to 2%). The change in epidemiology of CDI has been dramatic in recent years with an increasing incidence and severity in several countries according to the Centers for Disease Control (CDC)—in fact, the CDC has described CDI as a “global health challenge.” Over the past decade, solid-organ transplant recipients (SOTr) have been identified as a high-risk group. The incidence of CDI in SOTr ranges from 2% to 30%, depending on the organ type, with the greatest incidence in lung transplant recipients (LTr; 7% to 31%). An alarmingly high associated mortality of CDI in LTr (odds ratio 3.02, 95% confidence interval 2.71 to 3.36, p o 0.001) was demonstrated using multivariable regression analysis in a multi-institutional database of 449,000 SOTr with a 2.7% incidence of CDI. Gunderson and colleagues linked early CDI with the development of bronchiolitis obliterans syndrome in a single-center study; however, other outcome data, specifically in LTr with CDI, are currently lacking. After transplantation, diarrhea is a common non-specific symptom that can be caused by various etiologies, including medications and infection. If CDI is the cause, rapid and accurate diagnosis followed by prompt initiation of effective infection control and treatment measures is paramount to its eradication in LTr. In this issue of the journal, Lee and colleagues report on the impact of CDI on LTr in the largest single-center analysis to date. Again, an alarmingly high mortality was found to be associated with CDI in LTr in their study. Mortality correlated with early (o6 months) and late (46 months) CDI. The entire LTr cohort received prophylactic antibiotics, proton-pump inhibitors (PPIs) and immunosuppression as common denomi-

Postoperative antimicrobials after lung transplantation and the development of multidrug-resistant bacterial and Clostridium difficile infections: an analysis of 500 non-cystic fibrosis lung transplant patients.

Broad‐spectrum antimicrobials are given prophylactically post‐transplant, although these agents are a risk factor for multidrug‐resistant (MDR) infections and Clostridium difficile infection (CDI). This study aimed to determine whether an association exists between the duration of antimicrobials given early post‐transplant and the development of MDR infections or CDI.

IMMUNOSUPPRESSIVE REGIMEN FOR FIRST KIDNEY OR KIDNEY/PANCREAS TRANSPLANT SIGNIFICANTLY IMPACTS SENSITIZATION AT THE TIME OF SECOND TRANSPLANTATION.: 766

Introduction: A leading indication for kidney transplantation is failure of a previous renal allograft. Increased sensitization, measured by Panel Reactive Antibodies (PRA), results in prolonged waiting times for transplantation and makes it difficult, or in some cases, virtually impossible to place an organ without a positive crossmatch. This study aims to identify factors at the time of first transplant leading to increased sensitization in patients undergoing retransplantation. Methods: A review of UNOS kidney/pancreas transplant dataset #072309-2 (created 5/26/09) was performed. Retransplanted patients were identified and linked with the primary transplant event. Discharge immunosuppressive regimens from the first transplant event were also linked according to transplant ID. All retransplanted patients with a primary transplant date of 1999 or later, receiving either Thymoglobulin®, daclizumab or basiliximab (IL2-RA), or no induction at first transplant, and with a peak PRA at the time of first transplant of <20% were included. Subjects with missing or discrepant age, gender, transplant date, PRA values, or immunosuppression information were excluded. The final dataset was analyzed to identify factors that significantly impacted change in PRA (delta PRA) from the time of first to second transplant. Peak PRA values at the time of each transplant were used. Independent variables significantly associated with a delta PRA of 20% or lower were identified using logistic regression. Results: The final patient population (n=4218) had a mean (SD) age of 39±14 years at first transplant, and was 61% male, 73% Caucasian and 16% African American (AA). Initial transplant type was kidney (88.9%), simultaneous kidney-pancreas (8.7%), and pancreas alone (1.3%). Mean time between transplants was 3.2±2.5 years. Mean PRA at the time of first transplant was 1.9±3.6% and the mean delta PRA was 26±37% from first to second transplant. Induction immunosuppression for the primary transplant event was no induction (43%), Thymoglobulin® (24%), and IL2RA (33%). Discharge maintenance immunosuppressive therapy consisted of cyclosporine (30%) or tacrolimus (57%) combined with mycophenolate mofetil/sodium (MMF) (73%), rapamycin (13%), or azathioprine (3%) and steroids (80%). On univariate analysis, variables at the time of first transplant found to be significantly associated with a lesser delta PRA were Thymoglobulin® induction (23.9% vs. 26.9%, p=.004), tacrolimus maintenance (22.6% vs. 30.4%, p<.0001) and MMF maintenance (25.1 vs. 28.3, p=0.01). Variables significantly associated with a greater delta PRA were IL2RA induction (28.0% vs. 25.0%, p=0.02), cyclosporine maintenance (30.5% vs. 24.0%, p<0.001), and AA ethnicity (39.3% vs. 23.4%, p<0.001). Non-significant variables were age, gender, PRA at first transplant, rapamycin maintenance and steroid maintenance. Factors favoring a delta PRA < 20% in the multivariate analysis included Thymoglobulin® vs. IL2-RA induction (OR 0.766, p=0.007), tacrolimus vs. cyclosporine maintenance (OR 0.588, p<0.0001), and non-AA vs. AA ethnicity (OR 0.479, p<0.0001). Conclusion: Thymoglobulin® induction and tacrolimus maintenance therapy for primary kidney or pancreas transplant results in significantly reduced sensitization at the time of retransplantation, while AA race is associated with a greater change in PRA. This data suggests a possible long-term benefit to using Thymoglobulin® induction and tacrolimus maintenance therapy in primary renal or pancreas transplants with a low PRA.