Spencer T. Martin

Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation.

BACKGROUND AND OBJECTIVES Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. RESULTS A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. CONCLUSIONS This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.

Induction immunosuppressive therapies in renal transplantation

PURPOSE Induction immunosuppressive therapies for patients undergoing renal transplantation are reviewed. SUMMARY The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplantation. Induction therapy is often considered essential to optimize outcomes, particularly in patients at high risk for poor short-term outcomes. All of the induction immunosuppressive agents currently used are biological agents and are either monoclonal (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) or polyclonal (antithymocyte globulin [equine] or antithymocyte globulin [rabbit]) antibodies. Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent. Basiliximab is not considered as potent an immunosuppressive agent but has a much more favorable adverse-effect profile compared with antithymocyte globulin (rabbit) and is most commonly used in patients at low risk for acute rejection. Rituximab is being studied for use as induction therapy but to date has not demonstrated any significant benefits over placebo. While head-to-head data are available comparing most induction agents, the final decision on the most appropriate induction therapy for a transplant recipient is highly dependent on preexisting medical conditions, donor characteristics, and the maintenance immunosuppressive regimen to be used. CONCLUSION No standard induction immunosuppressive regimen exists for patients undergoing renal transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. The choice of regimen depends on the preferences of clinicians and institutions.

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.

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 systems 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, belatacepts limited adverse‐effect profile and convenient dosing strategy may make it an attractive option for immuno‐suppressive maintenance for both the patient and clinician.

Risk factors associated with Clostridium difficile infection after kidney and pancreas transplantation

Clostridium difficile infection (CDI) is a common cause of nosocomial antibiotic‐associated diarrhea with an increased incidence reported in solid organ transplant recipients. We sought to determine if kidney and/or pancreas transplant recipients possess unique risk factors for CDI.

Cytomegalovirus disease in lung transplantation: impact of recipient seropositivity and duration of antiviral prophylaxis

A recent randomized trial demonstrated that 1 year of antiviral prophylaxis for cytomegalovirus (CMV) after lung transplantation is superior to 3 months of treatment for prevention of CMV disease. However, it is uncertain if a shorter duration of prophylaxis might result in a similar rate of CMV disease among select lung transplant (LT) recipients who are at lower risk for CMV disease, based on baseline donor (D) and recipient (R) CMV serologies.

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.

Hepatitis B Reactivation and Rituximab: A New Boxed Warning and Considerations for Solid Organ Transplantation

Use of rituximab, a chimeric monoclonal antibody directed at the CD20 antigen, continues to increase in solid organ transplantation (SOT) for several off‐label uses. In September 2013, the United States Food and Drug Administration (FDA) issued a Drug Safety Communication to oncology, rheumatology and pharmacy communities outlining a new Boxed Warning for rituximab. Citing 109 cases of fatal hepatitis B virus (HBV) reactivation in persons receiving rituximab therapy with previous or chronic HBV infection documented in their Adverse Event Reporting System (AERS), the FDA recommends screening for HBV serologies in all patients planned to receive rituximab and antiviral prophylaxis in any patient with a positive history of HBV infection. There is a lack of data pertaining to this topic in the SOT population despite an increase in off‐label indications. Previous reports suggest patients receiving rituximab, on average, were administered six doses prior to HBV reactivation. Recommendations on prophylaxis, treatment and re‐challenging patients with therapy after resolution of reactivation remain unclear. Based on data from the FDA AERS and multiple analyses in oncology, SOT providers utilizing rituximab should adhere to the FDA warnings and recommendations regarding HBV reactivation until further data are available in the SOT population.

Atovaquone versus trimethoprim–sulfamethoxazole as Pneumocystis jirovecii pneumonia prophylaxis following renal transplantation

Pneumocystis pneumonia (PCP) is associated with significant morbidity and mortality in renal transplant recipients (RTR). Trimethoprim–sulfamethoxazole (TMP‐SMZ) is considered the prophylactic agent‐of‐choice. Some patients require an alternative owing to TMP‐SMZ intolerance. This is the first evaluation of full‐dose atovaquone vs. TMP‐SMZ for PCP prevention in RTR. One hundred and eighty‐five RTR were evaluated in this single‐center, retrospective analysis. Patients received either single‐strength TMP‐SMZ daily (group I; n = 160) or 1500 mg/d of atovaquone and of a fluoroquinolone for one month (group II; n = 25). The primary endpoint was the incidence of PCP at 12 months post‐transplant. There were no cases of PCP in either group. There were comparable rates of infections from bacterial pathogens and cytomegalovirus, but rates of BK viremia were significantly higher in group I (22.5%) vs. group II (4%; p = 0.03). The incidence of leukopenia was similar in both groups. Higher mean potassium levels were seen in group I at three months post‐transplant but were comparable at all other time points. The need for dose reduction and/or premature discontinuation of therapy secondary to adverse events was more prevalent in TMP‐SMZ‐treated patients. In our experience, atovaquone appears to be effective in preventing PCP post‐renal transplant and also demonstrates good tolerability.

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.