Valganciclovir (VGCV) followed by cytomegalovirus (CMV) hyperimmune globulin compared to VGCV for 200 days in abdominal organ transplant recipients at high risk for CMV infection: A prospective, randomized pilot study.

BACKGROUND: With the advent of effective antivirals against cytomegalovirus (CMV), use of CMV hyperimmune globulin (HIG) has decreased. Although antiviral prophylaxis in patients at high risk for CMV is effective, many patients still have late infection, never developing antibodies sufficient to achieve immunity. Utilizing a combination of antiviral and CMV HIG may allow patients to achieve immunity and decrease late CMV infections. METHODS: This was a prospective randomized, open-label, pilot study comparing valganciclovir (VGCV) prophylaxis for 200 days vs VGCV for 100 days followed by CMV HIG in abdominal transplant recipients at high risk for CMV. The primary outcome was a comparison of late CMV disease. RESULTS: Forty patients were randomized to VGCV for 200 days (n = 20) or VGCV for 100 days followed by 3 doses of monthly CMV HIG (n = 20). Numerically, more overall CMV infections occurred in the CMV HIG group (45 vs 20%, P = .09). No differences in overall CMV infections or late CMV disease were seen between groups (20% vs 15%, P = 1.00 and 0 vs 0, P = 1.00). All CMV disease occurred within 200 days, with 63% occurring while patients were on VGCV. No differences were found in toxicities, graft function, or rejection between groups. Patients with CMV infection at any time had a higher body weight than those who did not have an infection (82 vs 95 kg, P = .049). CONCLUSION: Use of CMV HIG sequentially with prophylaxis may be an effective and affordable prophylactic regimen in abdominal transplant recipients at high risk for CMV, and warrants larger prospective study. Increased monitoring for patients with obesity may be warranted.

Graft outcomes in pediatric kidney transplantation: focus on the role of race.

While significant racial disparities in graft outcome persist among adult and pediatric kidney transplant recipients in the US, some international studies do not show these differences. The aim of this study is to examine predictors of graft outcomes and the impact of race in our pediatric kidney transplant cohort. Records of 109 pediatric kidney transplant recipients performed at our institution between 7/99 and 4/07 were studied. Patients were grouped based on race: African-American (AA) vs. non-AA. Fifty-five AA (12 ± 5 years) and 54 non-AA patients (11 ± 6 years) were studied. There were more females, pre-emptive transplants and living donors in the non-AAs. Survival analysis showed significantly higher rejection rates in AAs, P = 0.02, and lower unadjusted graft survival (P = 0.09). Cox Proportional Hazards Survival Regression Analysis revealed biopsy-proven acute rejection and delayed graft function contributed to worse graft survival, while pre-emptive transplantation had a favorable effect. Race was not an independent risk factor for decreased graft survival in the final model. In conclusion, our cohort showed several modifiable risk factors that can partially account for poorer graft survival in pediatric AA kidney transplant recipients.

Novel strategies for immune monitoring in kidney transplant recipients.

The ongoing quandary in kidney transplantation is discovering methods to prolong graft survival. To achieve this, there is a search for optimal methods to use immunosuppressive therapy, where rejection and chronic graft damage is minimized without causing an increased risk of infections, malignancy, or toxicities. The purpose of this review was to discuss the limitations of current immunosuppressant drug monitoring as well as the clinical application of novel methods of monitoring both immunosuppressants and the immune reaction within the allograft.

Management of hypertension in renal transplant patients: a comprehensive review of nonpharmacologic and pharmacologic treatment strategies.

OBJECTIVE: To review the guidelines and literature for the treatment of hypertension in renal transplant patients and to provide guidance to practitioners in the selection of appropriate nonpharmacologic and pharmacologic treatment options. DATA SOURCES: A PubMed search (January 1948-March 2010) was performed using the search terms hypertension, antihypertensive agents, blood pressure, and cardiovascular disease, in combination with renal transplant and kidney transplant. The search was limited to articles published in English. All relevant peer-reviewed original studies, meta-analyses, guidelines, consensus statements, and review articles were examined. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All literature found was evaluated for inclusion. Review articles as well as prospective and retrospective original research articles were reviewed. DATA SYNTHESIS: Hypertension after solid organ transplantation is a problem commonly encountered in patients during their posttransplantation clinic visits. Effective management of these patients' hypertension is crucial, as hypertension left untreated may lead to increased morbidity and mortality as well as graft loss. The unique, multifactorial etiology of hypertension in this population makes treatment choices more challenging compared to treatment of a nontransplant patient. Therefore, to guide practitioners in this process, we developed a hypertension management protocol, taking into account the unique considerations faced in the adult renal transplant population. The review guides practitioners from the initial assessment of patients' hypertension through the evaluation and selection of nonpharmacologic and pharmacologic treatment options and provides information about the discontinuation of certain antihypertensive medications. It also provides a concise, but comprehensive review of the major antihypertensive drug classes and economic considerations. CONCLUSIONS: The management of hypertension in posttransplantation patients is challenging and complicated, yet necessary to prevent morbidity, mortality, and graft loss for these patients. Therapy should be individualized based on patient assessment, response to previous therapy, and economic considerations.

Can preemptive cytomegalovirus monitoring be as effective as universal prophylaxis when implemented as the standard of care in patients at moderate risk?

BACKGROUND: Cytomegalovirus (CMV) is a significant cause of morbidity, mortality, and cost in solid organ transplant recipients. This study was conducted to measure both the clinical efficacy and the pharmacoeconomic impact of implementing, as standard of care, an abbreviated preemptive monitoring strategy compared with universal prophylaxis in a large teaching hospital. METHODS: This prospective observational study included only recipients at moderate risk for CMV infection, specifically recipients who were CMV seropositive before transplant. Recipients transplanted between February 2006 and December 2006 received prophylactic valganciclovir for 90 days after transplant, and those transplanted between January 2007 and December 2007 were enrolled in a preemptive monitoring strategy that included no anti-CMV prophylaxis but instead used serial CMV polymerase chain reactions in weeks 4, 6, 8, 10, 12, 16, 20, and 24 to monitor the development of CMV DNAemia. Costs were analyzed from a societal perspective. RESULTS: A total of 130 patients were included in this study. Baseline and transplant demographics are well matched between groups. CMV syndrome occurred in three patients in each group, and one patient in the preemptive group developed CMV disease. Thirty-seven percent of patients in the preemptive group developed CMV DNAemia, 68% of these patients received antiviral therapy. Personnel and laboratory monitoring costs were significantly higher in the preemptive group, whereas medication cost was significantly higher in the prophylaxis group. CONCLUSIONS: Although outcomes and the overall cost of (1) universal prophylaxis and (2) preemptive monitoring are similar, universal prophylaxis places the cost burden on the patient whereas preemptive monitoring shifts the cost burden to the healthcare system.

Efficacy of induction therapy on acute rejection and graft outcomes in African American kidney transplantation.

BACKGROUND: African Americans (AA) have higher rejection rates and poorer graft outcomes compared to non-AAs. Induction therapy is yet unproven in this high risk population. METHODS: This retrospective study compared the efficacy of induction therapy [IL-2 receptor antibodies (IL2RA) or thymoglobulin] vs. no induction. RESULTS: One hundred and seventy-five AA patients were included in this analysis. Patients were well matched for demographic and immunologic characteristics in the non-induction and IL2RA induction groups; the Thymoglobulin induction group had significantly higher risk patients. Significantly fewer episodes of acute rejection occurred at one yr in patients treated with thymoglobulin and IL2RA vs. no induction (18% vs. 47%, p = 0.003, 26% vs. 47%, p = 0.02). Three yr graft survival was significantly improved in the IL2RA group compared to the non-induction group (85% vs. 68%, p = 0.032). Despite the thymoglobulin group being at high risk, they had similar graft survival rates compared to both the IL2RA group (76% vs. 85%, p = 0.18) and the non-induction group (76% vs. 68%, p = 0.48). Multivariate analysis demonstrated that induction therapy (combining IL2RA and thymoglobulin) independently reduced the risk of both acute rejection and graft loss. CONCLUSION: The use and type of induction therapy in AA patients significantly reduces acute rejection rates and may improve long-term graft outcomes in AA patients.

Comparison of efficacy of induction therapy in low immunologic risk African-American kidney transplant recipients.

African-Americans (AA) have higher acute rejection rates and poorer long-term graft survival rates when compared with non-AA. It is yet to be demonstrated that the type of induction therapy modifies outcomes in this 'high-risk' population. This retrospective analysis compares the efficacy of induction therapy [antilymphocyte antibodies (ALA) versus interleukin-2 receptor antagonists (IL-2RA)] in the AA population. Some 189 AAs were included. There was no difference in acute rejection at one year between the groups (ALA (12%) or IL-2RA (12%), P = 0.89). Type of induction therapy had no significant effect on death-censored (P = 0.61) or uncensored graft survival (P = 0.32). There was no difference between CMV or BK virus infections between the groups (P = 0.14 and 0.94 respectively). Type of induction therapy does not appear to affect acute rejection rates or long-term graft survival in low-risk AA kidney transplant recipients.

No difference between smokers, former smokers, or nonsmokers in the operative outcomes of laparoscopic donor nephrectomies.

The laparoscopic donor nephrectomy has revolutionized the living donation process for kidney transplantation. Because this surgery is elective and altruistic and smoking has been associated with greater technical difficulty and increased risk for postoperative complications for other types of surgeries, the potential risk of smoking must be addressed with regard to surgical complications. We reviewed 221 laparoscopic kidney donors with known smoking status. Forty-two (19%) were smokers, 39 (18%) were former smokers, and 140 (63%) were nonsmokers. Important donor demographics were similar between groups. There was no difference between the 3 groups for mean operative time (4.5 h vs. 4.6 h vs. 4.4 h), median or mean length of stay (2 days for all groups), estimated blood loss (173+/-137 mL vs. 209+/-184 mL vs. 188+/-198 mL), narcotic use (0.57+/-0.48 mg/kg vs. 0.49+/-0.26 mg/kg vs. 0.53+/-0.36 mg/kg of total 4 morphine equivalents), or postoperative complications. Smoking status does not seem to impact perisurgical patient outcomes in patients undergoing laparoscopic nephrectomies.

A prospective trial of a steroid-free/calcineurin inhibitor minimization regimen in human leukocyte antigen (HLA)-identical live donor renal transplantation.

BACKGROUND: Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transplantation exist. This prospective study evaluated a corticosteroid (CS)-free, calcineurin inhibitor (CNI) minimization immunosuppressive regimen in HLA-identical LD renal transplant recipients. METHODS: Twenty HLA-identical LD recipients were prospectively enrolled. Immunosuppression included mycophenolate mofetil (MMF) (2 g/day), tacrolimus (target trough 4-8 ng/mL), sirolimus (target trough 6-10 ng/mL), and no pre- or postoperative steroids. In the absence of prior rejection, tacrolimus was discontinued at posttransplant day 120 and sirolimus at 1 year, leaving patients on MMF monotherapy. RESULTS: Tacrolimus was successfully withdrawn in 94% of patients (16/17). One hundred percent (15/15) of patients who reached 1-year posttransplant had sirolimus discontinued. Ninety-four percent (17/18) of patients remain off CSs. Mean serum creatinine at 6, 12, and 24 months were 1.38+/-0.32, 1.35+/-0.37, and 1.25+/-0.29 mg/dL; corresponding mean calculated creatinine clearance estimates were 70+/-18, 73+/-17, and 72+/-15 mL/min. Acute cellular rejection, chronic allograft nephropathy, and CNI toxicity were not observed. Death-censored graft survival was 100% at last follow-up. CONCLUSIONS: A CS-free, CNI minimization immunosuppressive regimen with weaning to MMF monotherapy provides excellent renal function, graft survival, and patient survival in HLA-identical LD renal transplant recipients.

Renal transplantation in high-risk patients.

Renal transplantation in high-risk patients is a growing phenomenon. More patients are progressing to endstage renal failure, in the setting of an increased incidence of diabetes mellitus and cardiovascular disease. Current organ shortages and the use of more marginal donors have affected both patient and graft survival. Acute rejection has been minimised under modern immunosuppression; however, patient and long-term allograft outcomes have not improved concurrently. Specific understanding of donor, recipient and allograft variables associated with stratification of patients as 'high risk for renal transplantation' is necessary to facilitate appropriate peri- and post-transplant pharmacotherapy. Induction and maintenance immunosuppression choices are different for high-risk patients and must be made to ensure optimal immunosuppression, while limiting patient and allograft toxicity.

Monitoring of inosine monophosphate dehydrogenase activity as a biomarker for mycophenolic acid effect: potential clinical implications.

Mycophenolic acid (MPA) is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and, in combination with other immunosuppressive drugs, effectively inhibits rejection in solid organ transplant recipients. MPA has a relatively narrow therapeutic window and exhibits wide inter- and intrapatient pharmacokinetic (PK) variability. This has stimulated the use of therapeutic drug monitoring as a strategy to tailor the MPA exposure to each patient's individual needs. Despite increasing therapeutic drug monitoring use, PK-assisted dosing is not universally adopted in part because of MPA's complex PK behavior. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic (PD) marker of MPA-induced immunosuppression may allow for increased precision when used in an integrated PK-PD fashion, providing a more accurate assessment of efficacy and aid in limiting toxicity. IMPDH activity displays wide interpatient variability but relatively small intrapatient variability even after long-term administration of MPA. The advent of calcineurin and corticosteroid-sparing regimens necessitates more patient-specific PK-PD parameters, which can be used throughout the posttransplant period to optimize MPA exposure and immediate and long-term graft and patient outcomes. Quantification of IMPDH posttransplant may serve as a stable, surrogate PD marker of MPA-induced immunosuppression when combined with current PK and monitoring strategies.

Establishment of a nationalized, multiregional Paired Donation Network.

Over the past few years, significant progress has been made in the science and development of paired donation. With increasing awareness of paired donation and ready availability of the tools necessary to establish new consortia, paired donation can be made available to transplant programs and patients with increasing alacrity. Increasing registration of recipients and their donors for paired donation will lead to larger pools for matching and to transplantation of increasing numbers of patients via paired donation. As paired donation becomes common practice throughout the US and the international transplant community, its role in facilitating transplantation of sensitized patients will be better defined. Presently, paired donation remains an attractive alternative to desensitization and wait list paired donation for a majority of patients with preexisting humoral immunity to their donors.

Allopurinol as a cardioprotectant during coronary artery bypass graft surgery.

OBJECTIVE: To examine the role of allopurinol as a cardioprotectant during coronary artery bypass graft (CABG) surgery. DATA SOURCES: A search of MEDLINE (1966-October 2002) was performed using the following terms: allopurinol, xanthine oxidase, oxygen free radical, and coronary artery bypass. References evaluated were limited to English-language and human studies, yielding 41 citations, 13 of which were found suitable. The 5 largest studies are discussed. DATA SYNTHESIS: Multiple studies with various doses have evaluated the effects of allopurinol on outcomes in CABG patients. These studies found that allopurinol can reduce in hospital mortality, improve cardiac performance, reduce incidence of arrhythmias, reduce markers of ischemia and free-radical generation, and reduce the need for inotropic support. However, these findings were not consistent between all studies. CONCLUSIONS: Allopurinol may reduce the incidence of CABG complications. Although the optimal dose has not been determined, reviewed literature suggests that patients should receive at least 600 mg one day prior to surgery, as well as at least 600 mg on the day of surgery.

Smallpox: a review of clinical disease and vaccination.

The clinical course of smallpox infection and the current and future roles of vaccination and strategies for controlling smallpox outbreaks are reviewed. Close personal contact is required for transmission of variola, the DNA virus that causes smallpox. Following an incubation period, infected persons have prodromal symptoms that include high fever, back pain, malaise, and prostration. The eruptive stage is characterized by maculopapular rash that progresses to papules, then vesicles, and then pustules and scab lesions. The mortality rate for smallpox is approximately 30%. Patients having a fever and rash may be confused with having chickenpox. The most effective method for preventing smallpox epidemic progression is vaccination. Until recently, only 15 million doses of smallpox vaccine--manufactured 20 years ago--were available in the United States. The vaccine is a live vaccinia virus preparation administered by scarification with a bifurcated needle. The immune response is protective against orthopoxviruses, including variola. Vaccination is associated with moderate to severe complications, such as generalized vaccinia, eczema vaccinatum, progressive vaccinia, and postvaccinial encephalitis. Efforts for vaccine production are now focused on a live cell-culture-derived vaccinia virus vaccine. Although smallpox was eradicated in 1980, it remains a potential agent for bioterrorism. As a category A biological weapon, its potential to devastate populations causes concern among those in the public health community who have been actively developing plants to deal with smallpox and other potential agents of biological warfare. The only proven effective strategy against smallpox is vaccination.