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.

Impact of a Perioperative Prophylaxis Guideline on Post-Cardiothoracic Surgery Atrial Fibrillation.

BACKGROUND: National practice guidelines do not provide clear recommendations on combination pharmacological regimens to reduce cardiothoracic surgery (CTS) postoperative atrial fibrillation (POAF). OBJECTIVE: This study examines if there is a reduction in POAF rates after implementing a perioperative prophylaxis guideline that includes amiodarone, ß-blockers, and high-intensity statins. METHODS: Data were retrospectively collected on 400 adults (200 patients pre-guideline implementation and 200 patients post-guideline implementation) with a CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age, Diabetes Mellitus, and Vascular Disease) score of at least 3 points after CTS. Data were collected on the incidence of POAF lasting more than 5 minutes and secondary outcomes, including the length of hospitalization, guideline adherence rate, adverse events, and timeliness of POAF treatment. RESULTS: Guideline implementation increased prophylactic amiodarone ( P < 0.0001), statin ( P = 0.029), and high-intensity statin ( P = 0.002) use without changing ß-blocker use (64.5% vs 67.0%, P = 0.673) and reduced POAF (39.5% vs 52.0%, P = 0.016) and ventricular tachycardia (15.5% vs 24.5%, P = 0.034) compared with preguideline rates. Length of hospitalization and other postoperative adverse events, including stroke and mortality, were not statistically different. Subgroup analyses of patients who were adherent to both the amiodarone and ß-blocker recommendations (28% of the total) or to all 3 recommended therapies (24% of the total) had significant decreases in POAF ( P = 0.001; P < 0.001), length of hospitalization ( P = 0.023; P = 0.049), length of intensive care unit stay ( P = 0.045; P = 0.040), and ventricular tachycardia ( P = 0.008; P = 0.017) compared with preguideline patients, respectively. CONCLUSIONS: A perioperative guideline of amiodarone, ß-blockers, and high-intensity statins reduced POAF, but better benefits may result from enhanced adherence.

Intravenous Acetaminophen for Postoperative Pain Management in Patients Undergoing Living Laparoscopic Living-Donor Nephrectomy.

BACKGROUND: Postoperative pain is a common complication of laparoscopic living-donor nephrectomies (LLDNs). OBJECTIVE: To determine whether intravenous (IV) acetaminophen administration post-LLDN influenced length of stay (LOS) when used for pain management. METHODS: This single-center, retrospective study compared patients undergoing LLDN who had received IV acetaminophen for pain control versus those who did not between June 1, 2011, and November 30, 2015. Patient LOS, 30-day readmissions, frequency of pain assessments, patient-reported pain scores, and opioid administration were assessed. RESULTS: A total of 90 patients were included in the analysis (IV acetaminophen, n = 48; non-IV acetaminophen, n = 42). Patients who did not receive IV acetaminophen were more often older (48.8 ± 12.1 vs 39.3 ± 12.1 years; P = 0.012) and female (71.4% vs 47.9%; P < 0.001). The average LOS was similar between the 2 groups (median = 3.0; interquartile range = [3, 4] vs 3.5 [3, 4]; P = 0.737). The 30-day readmissions were higher in the IV acetaminophen group (16.7%) compared with the group not receiving IV acetaminophen (2.4%; P = 0.033). After the first postoperative day, the frequencies of pain assessments performed were similar among the 2 groups. There was no difference in average pain scores between the groups at any time after LLDN. CONCLUSIONS: Patients receiving IV acetaminophen were found to have no improvements in hospital LOS, average pain score, or opioid requirements compared with patients not receiving IV acetaminophen. Patients who received IV acetaminophen were also found to have a higher 30-day readmission rate.

Evaluation of Posttransplantation Diabetes Mellitus After Liver Transplantation: Assessment of Insulin Administration as a Risk Factor.

BACKGROUND: Impaired glucose regulation posttransplantation can affect allograft survival and may lead to the development of posttransplant diabetes mellitus (PTDM). OBJECTIVES: The primary purpose of this study is to assess the difference in insulin burden between liver transplant patients who develop PTDM and patients who do not. METHODS: This was a single-center, retrospective study. Adult liver transplant recipients transplanted between January 1, 2005, and August 1, 2013, were included. PTDM was defined as: (1) use of an oral antihyperglycemic agent for ≥30 consecutive days after transplant, (2) use of insulin ≥30 consecutive days after transplant, or (3) hemoglobin A1C≥6.5 any time after transplant. RESULTS: Of the 114 patients included, 48 (42%) developed PTDM. The average 24-hour insulin requirement on the medical floors was 17.2 ± 14.5 units in the PTDM group and 11.3 ± 12.2 units in the PTDM-free group;P= 0.02. The average blood glucose level on the medical floor was 184.7 ± 31.5 mg/dL in the PTDM group and 169.3 ± 31.4 mg/dL in the PTDM-free group;P= 0.013. Multivariate analysis revealed that experiencing rejection was positively associated with the development of PTDM: adjusted odds ratio (AOR) = 3.237; 95% CI = 1.214-8.633. Basiliximab was negatively associated with the development of PTDM: AOR = 0.182; 95% CI = 0.040-0.836. CONCLUSION: Univariate analyses suggest that insulin burden is a positive risk factor for the development of PTDM; this association is lost in multivariate analyses. Rejection was a positive predictor, and use of basiliximab was a negative predictor for the development of PTDM.

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.

Tolerability of low-dose sulfamethoxazole/trimethoprim for Pneumocystis jirovecii pneumonia prophylaxis in kidney transplant recipients.

Background- Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection seen in immunosuppressed patients, including solid-organ transplant recipients. Sulfamethoxazole/trimethoprim (SMX/TMP) has long been considered first-line therapy for PCP prophylaxis. Optimal dosing regimens in solid-organ transplant recipients have not been fully defined. Objective-To examine the tolerability of a 1-year, 3-times weekly, prophylactic regimen of a single-strength SMX/TMP tablet. Study Design-Single-center, retrospective cohort study. Setting-A tertiary-care medical center, including inpatient hospitalizations and outpatient transplant clinic visits. Patients-Adult patients who received a kidney transplant between December 1, 2010, and November 30, 2012, at Hartford Hospital. Patients receiving a concurrent extrarenal transplant were excluded. Patients' charts were reviewed for up to 1 year after transplant. Results-A total of 88 patients were included in the analysis. Sixty-seven patients finished a full year of SMX/TMP after transplant, 10 patients discontinued SMX/TMP less than 1 year after transplant, and 11 patients started taking atovaquone instead of SMX/TMP after transplant. Documented reasons for discontinuation included hyperkalemia, leukopenia, diarrhea, and simplification of medication regimen. Patients without a documented reason for discontinuation did not have any obvious anomalies in laboratory values that would account for the discontinuation. Patients who received atovaquone for PCP prophylaxis had higher rates of recurrent urinary tract infections than did patients who received SMX/TMP for prophylaxis (33% vs 7%, P = .02). A longer postoperative stay (median [interquartile range, IQR] 13 [8.25-26] days vs 7 [6-9.5] days, P = .02), higher rates of delayed graft function (50% vs 10%, P = .004), as well as higher serum creatinine levels on postoperative day 7 (6.25 [2.4-10.1] mg/dL vs 1.8 [1.2-4.2] mg/dL, P= .01), postoperative month 1 (1.9 [0.8] mg/dL vs 1.4 [0.5] mg/dL, P = .002), and postoperative month 12 (1.6 [0.5] mg/dL vs 1.3 [0.3] mg/dL, P = .04) were associated with early SMX/TMP discontinuation. Conclusion-A low-dose prophylactic SMX/TMP regimen of 1 single-strength tablet 3 times weekly is well tolerated. Discontinuation rates were lower than other rates reported for higher-dose regimens.

Acyclovir versus valganciclovir for preventing cytomegalovirus infection in intermediate-risk liver transplant recipients.

CONTEXT: Cytomegalovirus (CMV) is an opportunistic infection that causes profound morbidity and mortality after orthotopic liver transplant (OLT). The CMV immunoglobulin G serostatuses of donors and recipients are the main factors influencing risk for development of CMV infection after transplant. OBJECTIVE: To compare acyclovir and valganciclovir for preventing CMV infection after OLT. DESIGN, SETTING, AND PATIENTS: Retrospective assessment of adult OLT recipients at intermediate risk for CMV infection at New York Presbyterian Hospital. INTERVENTION: All patients received ganciclovir 5 mg/kg intravenously every 12 hours or valganciclovir 900 mg orally every 12 hours for 7 days after transplant. On postoperative day 8, patients received antiviral prophylaxis according to risk stratification: acyclovir 800 mg orally 3 times daily in donor seronegative/recipient seropositive (D-/R+) patients or valganciclovir 900 mg orally once daily in donor seropositive/recipient seropositive (D+/R+) patients. MAIN OUTCOME MEASURE: Composite incidence of CMV infection, syndrome, or tissue-invasive disease. RESULTS: Of 275 OLT recipients, 89 were at intermediate risk for CMV infection (29 D-/R+, 60 D+/R+). CMV infection, syndrome, or tissue-invasive disease occurred in 1 patient (3%) in the D-/R+ group and 5 patients (8%) in the D+/R+ group (P=.66). One patient (3%) in the D-/R+ group had a CMV infection develop. Five D+/R+ recipients (8%) had CMV infection; 3 of them had CMV syndrome (5%), 1 had CMV hepatitis (1.6%), and the other had CMV esophagitis (1.6%); all events occurred after prophylaxis was discontinued. The rates of CMV infection were similar in D-/R+ patients treated with acyclovir and D+/R+ patients receiving valganciclovir. This risk-stratified approach to viral prophylaxis after OLT resulted in an acceptable rate of CMV infection in D-/R+ recipients and may avoid the costs and adverse effects associated with valganciclovir therapy.

Clostridium difficile infection, a descriptive analysis of solid organ transplant recipients at a single center.

Clostridium difficile is a bacterial enteric pathogen, which causes clinical disease among solid organ transplant (SOT) recipients. This large, single-center, retrospective study describes incidence, demographics, and impact of C. difficile infection (CDI) among adult SOT recipients, cardiac (n=5), lung (n=14), liver (n=9), renal (n=26), and multiorgan (n=9) patients transplanted and diagnosed with CDI (geneB PCR) between 9/2009 and 12/2012. The overall incidence of CDI in our population during the 40-month period of study was 4%. CDI incidence among cardiac, lung, liver, and renal transplant recipients was 1.9%, 7%, 2.7%, and 3.2%, respectively (P=0.03 between organ-types). Median time from transplant to CDI for all was 51 (14-249) days, with liver recipients having the shortest time to infection, median 36 (15-101) days, and lung recipients having a longer time to infection, median 136 (29-611) days. Antibiotic exposure within 3 months of CDI was evident in 45 of the 63 (71%) patients in this study, 80%, 79%, 100%, 58%, and 67% of cardiac, lung, liver, renal, and multiorgan transplant recipients, respectively. Most patients (83%) were hospitalized within the 3 months preceding CDI. Recipients were followed for a median time of 23 (16-31) months; at the time of last follow-up, 83% of allografts were functioning, and 86% of patients were alive. One death and 1 graft failure were causally related to CDI. CDI had an overall incidence of 4%; clinicians should have heightened awareness for CDI, especially among patients receiving antibiotics, with increased monitoring and aggressive management of CDI.

Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab.

BACKGROUND: Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. METHODS AND RESULTS: We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). CONCLUSIONS: Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.

Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options.

Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients.

Risk evaluation and mitigation strategy programs in solid organ transplantation: the promises of information technology.

Risk evaluation and mitigation strategies (REMS) required by the Food and Drug Administration are implemented to manage known or potential risks associated with medications and to ensure ongoing safe use throughout the life of a pharmaceutical agent. Healthcare organizations have begun to adopt information technologies with clinical decision support (CDS) to ensure safe use of medications. Systems have been expanded and customized to also ensure compliance with regulatory standards. End users who are unfamiliar with particular medication use provisions are at risk of unknowingly inappropriately fulfilling specific components. Institution-specific customization of vendor-provided CDS is useful to enhance provider awareness and ensure compliance with standards. Integration of health information technology systems to fulfill REMS requirements is novel and important to ensure consistency as healthcare standards evolve.

Risk of posttransplant lymphoproliferative disorder associated with use of belatacept.

PURPOSE: Published evidence on a rare but serious malignancy associated with use of the first biological agent approved for long-term maintenance immunosuppression in renal transplant recipients is reviewed. SUMMARY: Belatacept (Nulojix, Bristol-Myers Squibb) is approved by the Food and Drug Administration for use in combination therapy to prevent renal graft rejection in patients who are Epstein-Barr virus seropositive. Belatacept appears to offer some advantages over calcineurin inhibitor-based regimens (e.g., no need for therapeutic drug monitoring), but its use poses a risk of posttransplant lymphoproliferative disorder (PTLD), a rapidly progressing and often lethal malignancy. The efficacy and safety of more-intensive and less-intensive belatacept regimens were established in two Phase III clinical trials, which found that rates of patient and graft survival were comparable to those in cyclosporine users; belatacept was shown to be superior in preserving renal function. The occurrence of PTLD, particularly PTLD involving the central nervous system, in 0-4% of belatacept-treated patients in clinical trials prompted postmarketing initiatives: (1) implementation of a risk evaluation and mitigation strategy (REMS) program to help ensure the safe and proper use of belatacept, (2) longitudinal studies to better define the risks and outcomes of belatacept therapy, and (3) a manufacturer-created patient registry to track belatacept use and encourage voluntary reporting of associated adverse events. CONCLUSION: Appropriate patient selection and adherence to REMS requirements, including patient counseling and facilitation of registry enrollment, are essential in mitigating the increased risk of PTLD associated with belatacept therapy.

Managing renal transplant ischemia reperfusion injury: novel therapies in the pipeline.

Ischemia reperfusion injury (IRI) is an early, non-specific inflammatory response that follows perfusion of warm blood into a cold asanguinous organ following transplantation. The occurrence of IRI may have a pivotal impact on acute and long-term renal allograft function. Initially, IRI contributes to delayed graft function (DGF), a term typically defined as the need for dialysis within one wk after renal transplantation. DGF frequently leads to prolonged hospital stay, increased healthcare costs, and potentially worse prognosis. Strategies to prevent IRI have so far been fairly limited, poorly defined, inadequately studied, and mostly anecdotal. The purpose of this review is to summarize the existing and novel therapies, which may mitigate IRI in renal transplantation. Agents currently in the pipeline include: Diannexin, which reduces endothelial cell injury by shielding phosphatidylserine; YSPSL, which mimics the binding portion of P-selectin glycoprotein ligand-1 to competitively inhibit translocation of P-selectin and recruitment of polymorphonuclear leukocytes to the surface of endothelial cells; and I5NP, a synthetic small interfering ribonucleic acid that results in the inhibition of p53 expression. These agents represent an exciting frontier in transplant pharmacotherapy; they are in various phases of investigation and may have broader benefits in reducing complications of DGF.

Enhancements in healthcare information technology systems: customizing vendor-supplied clinical decision support for a high-risk patient population.

Healthcare organizations continue to adopt information technologies with clinical decision support (CDS) to prevent potential medication-related adverse drug events. End-users who are unfamiliar with certain high-risk patient populations are at an increased risk of unknowingly causing medication errors. The following case describes a heart transplant recipient exposed to supra-therapeutic concentrations of tacrolimus during co-administration of ritonavir as a result of vendor supplied CDS tools that omitted an interaction alert. After review of 4692 potential tacrolimus-based DDIs between 329 different drug pairs supplied by vendor CDS, the severity of 20 DDIs were downgraded and the severity of 62 were upgraded. The need for institution-specific customization of vendor-provided CDS is paramount to ensure avoidance of medication errors. Individualized care will become more important as patient populations and institutions become more specialized. In the future, vendors providing integrated CDS tools must be proactive in developing institution-specific and easily customizable CDS tools.

Influenza in solid organ transplant recipients.

OBJECTIVE: To review available data describing the epidemiology, outcomes, prevention, and treatment of influenza virus in the solid organ transplant population and to evaluate the strengths and limitations of the current literature, with a focus on literature reviewing annual influenza strains and the recent pandemic novel influenza A/H1N1 strain. DATA SOURCES: A systematic literature search (July 1980-June 2011) was performed via PubMed using the following key words: influenza, human; influenza; novel influenza A H1/N1; transplantation; solid organ transplantation; kidney transplant; renal transplant; lung transplant; heart transplant; and liver transplant. STUDY SELECTION AND DATA EXTRACTION: Papers were excluded if they were not written in English or were animal studies or in vitro studies. Data from fully published studies and recent reports from international conferences were included. DATA SYNTHESIS: The influenza virus presents a constant challenge to immunocompromised patients and their health care providers. The annual influenza strain introduces a highly infectious and pathogenic risk to solid organ transplant recipients. In 2009, the World Health Organization declared a pandemic as a result of a novel influenza A/H1N1 strain. The pandemic introduced an additional viral threat to solid organ transplant patients at increased risk for infectious complications. The mainstay for prevention of influenza infection in all at-risk populations is appropriate vaccination. Antiviral therapies against influenza for chemoprophylaxis and treatment of infection are available; however, dosing strategies in the solid organ transplant population are not well defined. CONCLUSIONS: The solid organ transplant population is at an increased risk of severe complications from influenza infection. Identifying risks, preventing illness, and appropriately treating active infection is essential in this patient population.

Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal.

STUDY OBJECTIVE: To compare the safety and efficacy of rabbit antithymocyte globulin (r-ATG) with basiliximab in renal transplant recipients for whom an early steroid withdrawal (ESW) regimen was planned. DESIGN: Single-center, retrospective, cohort study. SETTING: Tertiary care medical center, including inpatient hospital stays and outpatient nephrology clinics. PATIENTS: Ninety-nine consecutive adult recipients of living- or deceased-donor renal transplants between January 1, 2004, and December 31, 2007, in whom ESW was planned and who received either r-ATG or basiliximab; patients receiving an extended-criteria kidney donation or a donation after cardiac death were excluded. MEASUREMENTS AND MAIN RESULTS: All patients received mycophenolate mofetil and tacrolimus as maintenance therapy with planned ESW. Induction therapy was either r-ATG 1.5 mg/kg/day for 4 days (68 patients) or basiliximab 20 mg on postoperative days 0 and 4 (31 patients). The primary composite end point of biopsy-proven acute rejection (BPAR), graft loss, and death occurred in 6 patients (9%) and 9 patients (29%) in the r-ATG and basiliximab groups at 1 year after transplantation, respectively (p=0.01), with rates of 7% (5/68 patients) and 26% (8/31 patients) for BPAR (p=0.02), 0% and 3% (1/31 patients) for graft loss (p=0.31), and 2% (1/68 patients) and 0% for patient death (p>0.99). Average time to first BPAR was significantly longer in the r-ATG group (mean ± SD 151.4 ± 82.9 vs 53.6 ± 68.4 days, p<0.01). Kidney function at 12 months was similar between the two groups. CONCLUSION: Rabbit-ATG was associated with a lower frequency and delayed onset of BPAR compared with basiliximab in renal transplant recipients who received an ESW regimen.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

OBJECTIVE: To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation. CASE SUMMARY: The first patient is a 52-year-old female with a history of intolerance to calcineurin inhibitors (CNIs) and sirolimus. Following her second transplant, the patient received mycophenolate mofetil 100 mg twice daily, a tapering corticosteroid regimen (initial dose of methylprednisolone 500 mg tapered over 1 week to prednisone 30 mg/day), and biweekly intravenous daclizumab 1-1.2 mg/kg/dose; 33 months after transplant the IL-2RA was changed to intravenous basiliximab 40 mg once a month. At 40 months after transplant, the patient continued to have stable renal function (estimated glomerular filtration rate 48 mL/min/1.73 m²) with excellent tolerability. The second patient is a 59-year-old female also intolerant to CNIs and sirolimus who required intermittent maintenance therapy with intravenous basiliximab 20 mg/dose. Despite an initial rejection episode, the patient tolerated more than 2 years of basiliximab therapy with good renal function (estimated glomerular filtration rate 103 months after transplant 69 mL/min/1.73 m²) and no adverse events. DISCUSSION: The IL-2RAs basiliximab and daclizumab possess several characteristics of ideal maintenance immunosuppressive agents (ie, nondepleting, long half-lives, limited adverse events). Based on a MEDLINE search (through December 31, 2010) using the search terms basiliximab, daclizumab, organ transplant, immunosuppression, and/or maintenance immunosuppression, and an advanced search in the published abstracts from the American Transplant Congress and World Transplant Congress (2000-2010), it appears that IL-2RAs have been used successfully as short-term therapy in both renal and extrarenal transplant recipients to allow for renal recovery following CNI-induced nephrotoxicity. In heart transplant recipients, the IL-2RAs have been used for <24 months as maintenance immunosuppression in patients intolerant of CNIs or sirolimus. CONCLUSIONS: To the best of our knowledge, these 2 cases are the first to demonstrate that IL-2RAs can be used as an alternative to a CNI in a de novo immunosuppressive regimen. Also, this is the first report to illustrate successful long-term use of IL-2RAs in renal transplant recipients. This alternative approach was well tolerated by our patients, with no apparent adverse events. Although the efficacy of such regimens cannot be determined with 2 case reports, the fact that intermittent intravenous IL-2RA administration was successfully accomplished in these patients provides impetus to evaluate this treatment modality in prospective studies.

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation.

In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as immunosuppressive maintenance therapy. Aside from an increased risk of malignancy, belatacept's limited adverse-effect profile and convenient dosing strategy may make it an attractive option for immuno-suppressive maintenance for both the patient and clinician.