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Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70 years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1-year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immuno-reactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under- and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long-term outcomes during the next era of immunosuppression, which will move from universal protocols to patient-specific optimization.

Cannabis, or marijuana, comprises many compounds with varying effects. It has become a treatment option for chronic diseases and debilitating symptoms, and evidence suggests that it has immunomodulatory and antiinflammatory properties. Transplant centers are more frequently facing issues about cannabis, as indications and legalization expand. As of February 2020, 33 states and the District of Columbia have legalized medical cannabis, and 14 have legalized recreational cannabis. Moreover, 8 states have passed legislation prohibiting the denial of transplant listing solely based on cannabis use. Studies demonstrate the potential for significant pharmacokinetic and pharmacodynamic interactions between cannabis and immunosuppression. Additionally, safety concerns include increased risk of myocardial infarction, ischemic stroke, tachyarrhythmias, malignancy, neurocognitive deficits, psychosis, other neuropsychiatric disorders, cannabis use disorder, respiratory symptoms, and infection. A recent retrospective database study found a negative association between documented cannabis use disorder and graft survival, but little additional evidence exists evaluating this relationship. In the absence of robust clinical data, transplant centers need a clear, reasoned, and systematic approach to cannabis. The results of our national survey, unfortunately, found little consensus among institutions. As both recreational and medicinal cannabis become more ubiquitous nationwide, transplant centers will need to develop comprehensive policies to address its use.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Viruses are the leading cause of infections after solid organ transplant. The antiviral properties of mammalian target of rapamycin inhibitors (mTORis) have been ascribed to a variety of mechanisms and historical data have supported their use over other immunosuppressants for a myriad of viruses. Herein, we summarize the most current data to highlight the role of mTORis in the management of viral infections after solid organ transplant. The mTORis play a clear role in the management of cytomegalovirus, and have data supporting their potential use for BK virus and human herpesvirus 8-related Kaposi sarcoma. No data definitively supports mTORis for use in Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder or hepatitis C virus viral replication. Although theoretically an advantageous therapy for hepatitis C virus-related liver allograft fibrosis and human immunodeficiency virus, mTORi use specifically for these indications is less attractive with modern treatments currently available. Data surrounding mTORi efficacy in preventing rejection, and their toxicity profile must be balanced with their potential antiviral effects in combination with patient-specific factors.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in immunocompromised patients. Available antivirals are fraught with adverse effects and risk for the development of CMV resistance. Letermovir is a novel antiviral in the late stages of drug development for the treatment and prevention of CMV. Areas covered: A MEDLINE search of the MeSH terms 'letermovir,' 'cytomegalovirus,' 'hematopoietic stem cell transplant,' and 'solid organ transplant,' was last conducted on 15 August 2016. Articles were selected on the basis of their contribution to current knowledge about letermovir. Expert opinion: Letermovir's mechanism of action, pharmacokinetic and pharmacodynamic profile, and favorable efficacy and safety make it an attractive option for both the prevention and treatment of CMV in immunocompromised patients. The lack of cross-resistance with other antivirals and the absence of myelosuppression are two prominent characteristics of letermovir that could support broad use of this product following FDA-approval. One major limitation is its lack of activity against other herpesviruses, which are commonly seen in immunocompromised hosts. We believe that with additional clinical efficacy data, this medication could emerge as a primary option for the prevention and treatment of CMV in the immunocompromised patient population.

Tacrolimus-induced cardiomyopathy (TICM) is a rare but serious adverse effect of tacrolimus, which has been described primarily in pediatric non-renal transplant recipients. We describe a case of TICM in an adult renal transplant recipient that resulted in allograft dysfunction and multiple hospital admissions for heart failure exacerbation. Prompt and complete reversal of TICM occurred after tacrolimus discontinuation. Although tacrolimus-induced cardiomyopathy is reversible, availability of alternative immunosuppressants is limited, particularly in the setting of renal dysfunction. Available studies and patient-specific factors must be considered when determining an alternative maintenance immunosuppression regimen. We chose to use belatacept as alternative immunosuppression in this patient with TICM. Over the next 3 years, the patient remained free of hospital admissions and acute rejection, and demonstrated superior renal allograft function than was observed before her first heart failure admission. We believe that belatacept is an acceptable alternative to tacrolimus therapy for resolution of TICM.

Introduction: Rabbit antithymocyte globulin (ATG) has become the most widely used lymphocyte-depleting agent in solid organ and hematopoietic stem cell transplantation. Its use in kidney transplantation for inducing immunosuppression and treating rejection has led to prolonged allograft and patient survival.Areas covered: A MEDLINE search of the MeSH terms ‘thymoglobulin,’ ‘rabbit antithymocyte globulin,’ ‘renal transplantation,’ ‘kidney transplantation,’ ‘induction’ and ‘rejection’ was last conducted on 18 April 2014. Appropriate articles were selected, with priority given to randomized controlled trials and meta-analyses, in order to summarize the current knowledge of the drug and discuss the clinical efficacy of thymoglobulin in the renal allograft.Expert opinion: Rabbit ATG has been used successfully and relatively safely in renal transplantation for over 30 years. It has a durable and profound lymphocyte-depleting effect, offering superior outcomes for immunosuppression induction and for the treatmen...

Background Invasive fungal infections (IFI) remain a significant cause of morbidity and mortality in orthotopic liver transplantation (OLT) recipients. In this retrospective study, the outcomes of a protocol using once weekly fluconazole for 3 months after OLT in low‐ and high‐risk patients were reviewed. Methods In total, 221 OLTs were evaluated in the 3‐year period after institution of the new protocol to determine the incidence of IFI within 6 months post‐OLT. Results In this cohort, 11 IFIs developed during the 6‐month post‐transplant period, with the majority being non‐albicans Candida. High‐risk patients had a greater rate of IFI (16.7% versus 3.4%, P = 0.038) and a significantly longer intensive unit care (ICU) and hospital lengths of stay compared with low‐risk patients. Patient and graft survival were similar between the groups. Our patient population appeared to be at low risk for IFI, with 92% of the entire cohort considered low risk. Discussion Given the low incidence of IFI in the low‐risk group and the possibility of such protocol selecting out for fluconazole‐resistant fungi, the use of weekly fluconazole for 3 months may not be justifiable in low‐risk OLT recipients. Given the increased resource utilization observed with IFI, further examination of a more intensive prophylactic strategy in high‐risk patients may be warranted.

The presence of pharmacists on multidisciplinary transplantation teams is well established.[1][1] The mandates outlined by the Centers for Medicare and Medicaid Services (CMS) and the Organ Procurement and Transplantation Network/United Network for Organ Sharing bylaws have resulted in nearly

Background: The topical use of thrombin has a long history in surgery as an adjunct for achieving operative hemostasis. Until recently the majority of thrombin used topically was derived from bovine plasma. This preparation has been proven to be immunogenic and has led to safety concerns in recent years. Recombinant human thrombin (rhThrombin) has recently been developed as an alternative for topical use for surgical hemostasis. Objective: To review the clinical safety and efficacy data relating to rhThrombin using bovine-derived thrombin as a comparative standard. Methods: This review summaries recent literature regarding topical use of rhThrombin using bovine thrombin as the ‘gold standard’ for topical surgical hemostasis. Conclusions: The data indicates that topical rhThrombin is as effective as bovine thrombin for hemostasis and significantly less immunogenic.

Complex cardiovascular surgery often results in postoperative hemorrhage. Excessive blood product use may cause systemic thrombosis, end-organ dysfunction, and edema preventing chest closure. Recombinant activated factor VII (rFVIIa) concentrate may decrease hemorrhage where other treatment measures failed. We reviewed our experience with rFVIIa after complex cardiovascular surgery.A retrospective review evaluating 846 complex cardiovascular surgery patients of whom 36 received rFVIIa between January 1, 2001, and December 31, 2006, was performed. Efficacy and safety data were collected for the entire cohort in addition to delayed sternal closure requirements, reoperation, and operative mortality in the patient cohort temporally separated into two groups (pre-rFVIIa era, 2001 to 2003, 1 patient received rFVIIa; rFVIIa era, 2004 to 2006, 35 patients received rFVIIa).A total of 36 patients received 41 rFVIIa doses with an in-hospital survival of 91.7%. Hemorrhage was controlled in 83.3% of patients, with 1 dose sufficient in 75.0%. There was a significant decrease (p0.005) in all blood product requirements post-rFVIIa compared with pre-rFVIIa administration. In the intensive care unit (n = 6), rFVIIa significantly reduced chest tube output (p = 0.028) and prevented reexploration for bleeding in 5 patients. The requirement for delayed sternal closure was significantly higher in the pre-rFVIIa era versus the rFVIIa era (p = 0.011). The incidence of thrombosis in all patients receiving rFVIIa was 11.1%. In the rFVIIa era, a higher incidence of postoperative renal failure (p = 0.005) and pneumonia (p0.002) was detected in patients receiving rFVIIa.Recombinant activated factor VII appears to be effective in patients with refractory coagulopathy undergoing high-risk cardiovascular surgery.

Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.

Whereas the reactions between either NdI2 or TmI2 and 1 equiv of the dipotassium salt [{(Me3Si)2C(SiMe2)}2O]K2(OEt2) (2) yield only intractable mixtures of products, reactions between LnI2 and 1 equiv of {(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2K2 (3) yield the lanthanide(III) compounds {(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2Ln(OMe)(THF) [Ln = Tm (9), Nd (10)] via a ligand degradation reaction. In contrast, YbI2 reacts smoothly with either 2 or 3 to give the ytterbium(II) alkyls [{(Me3Si)2C(SiMe2)}2O]Yb(THF)2 (4) and {(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2Yb(THF) (5), respectively, in excellent yields. Compounds 4 and 5 have been characterized by multielement (1H, 13C{1H}, 29Si, and 171Yb) NMR spectroscopy, and compounds 4, 5, 9, and 10 by elemental analyses and X-ray crystallography. Compounds 9 and 10 crystallize as structurally similar monomers with a distorted trigonal prismatic geometry about the Ln(III) ions; in 4 and 5 the Yb centers lie in a distorted trigonal bipyramidal geometry. Compound 5, although potentially diastere...

The reaction between LnI 3 (THF) 3.5 and 2 equiv. of {(Me 3 Si) 2 (Me 2 MeOSi)C}K ( 1 ) in THF at room temperature yields only the mono-substituted products {(Me 3 Si) 2 (Me 2 MeOSi)C}LnI 2 (THF) 2 [Ln = Y ( 5 ), Tm ( 6 )]; under more forcing conditions decomposition occurs. In contrast, the metathesis reaction between TmI 3 (THF) 3.5 and 2 equiv. of the lithium iodide-containing salt {(Me 3 Si) 2 (Me 2 MeOSi)C}K(LiI) x yields the highly unusual separated ion pair complex [[{(Me 3 Si) 2 C(SiMe 2 )} 2 O]TmI 2 {Li(THF) 3 } 2 ][[{(Me 3 Si) 2 C(SiMe 2 )} 2 O]TmI 2 ] ( 8 ). The dianionic ligand in 8 is derived from the coupling of 2 equiv. of (Me 3 Si) 2 (Me 2 MeOSi)C − , accompanied by the formal elimination of Me 2 O. The structures of compounds 5 , 6 , and 8 have been determined by X-ray crystallography; compound 8 crystallizes as an unusual ion pair, the cation and anion of which differ only in the inclusion of 2 equiv. of Li(THF) 3 in the former, bridged to thulium by iodide ions.

Metathesis reactions between LaI3(THF)4 and either 2 equiv of [(Me3Si)2{Me2(Me2N)Si}C]K or 1 equiv of {(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2K2 in THF yield the heteroleptic lanthanum dialkyls [(Me3Si)2{Me2(Me2N)Si}C]2LaI (3) and [{(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2]LaI(THF) (5), respectively. In contrast, the reaction between LaI3(THF)4 and 2 equiv of [(Me3Si)2{Me2(MeO)Si}C]K in THF, under a variety of reaction conditions, gives a mixture of the mono- and disubstituted compounds [(Me3Si)2{Me2(MeO)Si}C]LaI2(THF) (7) and [(Me3Si)2{Me2(MeO)Si}C]2LaI(THF) (8), which cannot be separated by crystallization. The reaction between this mixture and 1 equiv of KN(SiMe3)2 yields the heteroleptic complex [(Me3Si)2{Me2(MeO)Si}C]LaI{N(SiMe3)2}(THF) (9). While exact analogues of 3, 5, 8, and 9 could not be isolated for neodymium, a metathesis reaction between NdI3(THF)3.5 and the lithium iodide containing potassium alkyl {(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2K2·xLiI in THF yields the ate complex {(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2Nd(μ-I)2Li(T...

Background/Aims: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. Methods: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) 50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. Results: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). Conclusion: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Background The use of potent immunosuppression increases the risk of infectious complications following kidney transplantation. Sulfamethoxazole-trimethoprim (SMX/TMP) is an inexpensive broad-spectrum antimicrobial agent used in our center as lifelong prophylaxis against Pneumocystis jirovecii, unless contraindicated. This study evaluated the clinical impact of SMX/TMP prophylaxis compared with no prophylaxis with SMX/TMP (NoPPx), but with alternative agents. Methods This was a retrospective cohort analysis of renal transplant recipients (RTR) transplanted from January 2002 through December 2010. Patients were divided into SMX/TMP group and NoPPX group, based on whether they received prophylaxis with SMX/TMP or not, and rates of sepsis were compared between groups. We also analyzed the pathogens and source implicated in these episodes, as well as the dose of SMX/TMP. Rates were compared using multivariate logistic regression. Results With a mean follow-up of 4.8 (± 2.5) years, 63 cases of sepsis occurred in 1224 patients (5.1%), and 60% of these cases had a urinary source. The risk of sepsis was significantly reduced with prophylaxis vs. NoPPx (13.3% vs. 4.3% for SMX/TMP, P

The achievement of hemostasis is paramount, and good operative practice is crucial to all surgical procedures. Intraoperative hemostasis is usually achieved through suture ligation for larger vessels and electrocautery of smaller vessels; certain cases, however, are not amenable to these techniques, especially when there is diffuse raw surface bleeding. When operative hemorrhage exists despite appropriate preventive actions and good surgical technique, additional methods for controlling intra- and perioperative hemorrhage should be considered, and may include the use of topical thrombin. Recombinant human thrombin (rhThrombin) was approved by the Food and Drug Administration in 2008, with the expectation of overcoming the disadvantages of previously available topical thrombin preparations. The efficacy of rhThrombin has been demonstrated in three randomized controlled trials and found to be effective for achieving hemostasis within 10 minutes of administration for mild to moderate diffuse raw surface bleeding. rhThrombin is equally as effective as bovine thrombin, with a significantly lower risk of immunogenicity. Similar economic parameters, efficacy, and safety profiles between rhThrombin and other available thrombin preparations may support its use over other bovine- and plasma-derived human thrombin products and carry limited to no risk of viral transmission or development of antithrombin antibodies.

A straightforward Peterson olefination reaction between either [{(Me(2)PhSi)(3)C}Li(THF)] or in situ-generated [(Me(3)Si)(2){Ph(2)P(BH(3))}CLi(THF)(n)] and paraformaldehyde gives the alkenes (Me(2)PhSi)(2)C[double bond, length as m-dash]CH(2) () and (Me(3)Si){Ph(2)P(BH(3))}C[double bond, length as m-dash]CH(2) (), respectively, in good yield. Ultrasonic treatment of with lithium in THF yields the lithium complex [{(Me(2)PhSi)(2)C(CH(2))}Li(THF)(n)](2) (), which reacts in situ with one equivalent of KOBu(t) in diethyl ether to give the potassium salt [{(Me(2)PhSi)(2)C(CH(2))}K(THF)](2) (). Similarly, ultrasonic treatment of with lithium in THF yields the lithium complex [[{Ph(2)P(BH(3))}(Me(3)Si)C(CH(2))]Li(THF)(3)](2).2THF (). The bis(phosphine-borane) [(Me(3)Si){Me(2)(H(3)B)P}CH(Me(2)Si)(CH(2))](2) () may be prepared by the reaction of [Me(2)P(BH(3))CH(SiMe(3))]Li with half an equivalent of ClSiMe(2)CH(2)CH(2)SiMe(2)Cl in refluxing THF. Metalation of with two equivalents of MeLi in refluxing THF yields the lithium complex [[{Me(2)P(BH(3))}(Me(3)Si)C{(SiMe(2))(CH(2))}]Li(THF)(3)](2) (), whereas metalation with two equivalents of MeK in cold diethyl ether yields the potassium complex [[{Me(2)P(BH(3))}(Me(3)Si)C{(SiMe(2))(CH(2))}](2)K(2)(THF)(4)](infinity) () after recrystallisation. X-Ray crystallography shows that, whereas the lithium complex crystallises as a discrete molecular species, the potassium complexes and crystallise as sheet and chain polymers, respectively.

The oxygen-bridged, silicon-substituted alkane {(Me3Si)2CH(SiMe2)}2O (1) may be prepared by the reaction of {(Me3Si)2CH}Li with ClSiMe2OSiMe2Cl in refluxing THF. Similarly, the alkane {(Me3Si)(Me2MeOSi)CH(SiMe2CH2)}2 (2) is readily accessible from the reaction between {(Me3Si)(Me2MeOSi)CH}Li and ClSiMe2CH2CH2SiMe2Cl under the same conditions. Compound 1 reacts with two equivalents of MeK to give the polymeric complex [[{(Me3Si)2C(SiMe2)}2O]K2(OEt2)]infinity [5(OEt2)] after recrystallisation. Treatment of 2 with two equivalents of either MeLi or MeK gives the corresponding complexes [{(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2Li][Li(DME)3] [7(DME)3] and [{(Me3Si)(Me2MeOSi)C(SiMe2CH2)}2K2]n (8), respectively, after recrystallisation. Treatment of the alkane (Me3Si)2(Me2MeOSi)CH with one equivalent of MeK gives the polymeric complex [{(Me3Si)2(Me2MeOSi)C}K]infinity (3). These compounds have been identified by 1H and 13C{1H} NMR spectroscopy and elemental analyses and compounds 5(OEt2), 7(DME)3 and 3 have been further characterised by X-ray crystallography. Compound 7(DME)3 crystallises as a solvent-separated ion pair, whereas 5(OEt2) and 3 adopt polymeric structures in the solid state.