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Background The development of cytomegalovirus (CMV) infection after kidney transplant remains a significant cause of posttransplant morbidity, graft loss, and mortality. Despite appropriate antiviral therapy, recipients without previous CMV exposure can currently be allocated a kidney from a donor with previous CMV infection (D+R-) which carries the greatest risk of posttransplant CMV infection and associated complications. Preferential placement of CMV D- organs in negative recipients (R-) has been shown to reduce the risk of viral infection and associated complications. Methods To assess the long-term survival and economic benefits of allocation policy reforms, a decision analytic model was constructed to compare receipt of CMV D- with CMV D+ organ in CMV R- recipients using data from transplant registry, Medicare claims, and pharmaceutical costs. Results For CMV R- patients, receipt of a CMV D- organ was associated with greater average survival (14.3 vs 12.6 years), superior quality-adjusted life years (12.6 vs 9.8), and lower costs ($529 512 vs $542 963). One-way sensitivity analysis demonstrated a survival advantage for patients waiting as long as 30 months for a CMV D- kidney. Conclusions Altering national allocation policy to preferentially offer CMV D- organs to CMV R- recipients could improve survival and lower costs after transplant if appropriately implemented.

Background Cannabis is categorized as an illicit drug in most US states, but legalization for medical indications is increasing. Policies and guidance on cannabis use in transplant patients remain controversial. Methods We examined a database linking national kidney transplant records (n = 52 689) with Medicare claims to identify diagnoses of cannabis dependence or abuse (CDOA) and associations [adjusted hazard ratio (aHR) with 95% upper and lower confidence limits (CLs)] with graft, patient, and other clinical outcomes. Results CDOA was diagnosed in only 0.5% (n = 254) and 0.3% (n = 163) of kidney transplant recipients in the years before and after transplant, respectively. Patients with pretransplant CDOA were more likely to be 19 to 30 years of age and of black race, and less likely to be obese, college-educated, and employed. After multivariate and propensity adjustment, CDOA in the year before transplant was not associated with death or graft failure in the year after transplant, but was associated with posttransplant psychosocial problems such as alcohol abuse, other drug abuse, noncompliance, schizophrenia, and depression. Furthermore, CDOA in the first year posttransplant was associated with an approximately 2-fold increased risk of death-censored graft failure (aHR, 2.29; 95% CL, 1.59-3.32), all-cause graft loss (aHR, 2.09; 95% CL, 1.50-2.91), and death (aHR, 1.79; 95% CL, 1.06-3.04) in the subsequent 2 years. Posttransplant CDOA was also associated with cardiovascular, pulmonary, and psychosocial problems, and with events such as accidents and fractures. Conclusions Although associations likely, in part, reflect associated conditions or behaviors, clinical diagnosis of CDOA in the year after transplant appears to have prognostic implications for allograft and patient outcomes. Recipients with posttransplant CDOA warrant focused monitoring and support.

BACKGROUND The first year after heart transplantation (HT) has the highest risk of mortality. We aim to derive and validate a recipient risk prediction tool for early mortality after pediatric HT. METHODS The International Society for Heart and Lung Transplantation (ISHLT) registry was used to identify patients (≤18 y) who underwent primary HT during January 2000-December 2014. Independent predictors of 1-year mortality were identified based on recipient characteristics at HT. Risk scores were assigned based on the magnitude of relative odds of 1-year mortality. The predictive capability of the ISHLT registry derived recipient risk score was externally validated using the Scientific Registry of Transplant Recipients registry data from 2015 to 2017 to ensure a cohort of patients completely exclusive from the derivation cohort. RESULTS A total of 5045 eligible patients were included in the analysis. The 20-point risk scoring system incorporated 8 recipient variables, including age at HT, diagnosis, pre-HT ventilator use, extracorporeal membrane oxygenation, inhaled nitric oxide use, infection, estimated glomerular filtration rate, and serum bilirubin. Compared with low-risk score group, high-risk group had 7-fold increased risk of 1-year mortality (hazard ratio 7.4; 95% CI [5.2-9.1]; P < 0.001). The C-statistics (0.77) and Hosmer-Lemeshow goodness of fit (0.9) for recipient risk score using derivation cohort from ISHLT registry performed well and was similar to the internal and external validation cohort (C-statistics 0.75, 0.78 and Hosmer-Lemeshow goodness of fit P = 0.4, 0.3, respectively). CONCLUSIONS This study derived and externally validated a simple risk predictive model based on recipient characteristics at HT that has good prediction characteristics for 1-year post-HT mortality. This model may help clinicians identify candidates who are at a higher risk for post-HT mortality and may optimize organ sharing.

Midodrine is prescribed to prevent symptomatic hypotension and decrease complications associated with hypotension during dialysis. We hypothesized that midodrine use before kidney transplantation may be a novel marker for posttransplant risk.We analyzed integrated national US transplant registry, pharmacy records, and Medicare claims data for 16 308 kidney transplant recipients transplanted 2006 to 2008, of whom 308 (1.9%) had filled midodrine prescriptions in the year before transplantation. Delayed graft function (DGF), graft failure, and patient death were ascertained from the registry. Posttransplant cardiovascular complications were identified using diagnosis codes on Medicare billing claims. Adjusted associations of pretransplant midodrine use with complications at 3 and 12 months posttransplant were quantified by multivariate Cox or logistic regression, including propensity for midodrine exposure.At 3 months, patients who used midodrine pretransplant had significantly (P0.05) higher rates of DGF, 32% versus 19%; hypotension, 14% versus 4%; acute myocardial infarction, 4% versus 2%; cardiac arrest, 2% versus 0.9%, graft failure, 5% versus 2%; and death, 4% versus 1% than nonusers. After multivariate adjustment including recipient and donor factors, as well as for the propensity of midodrine exposure, pretransplant midodrine use was independently associated with risks of DGF (adjusted odds ratio, 1.78; 95% confidence interval [CI], 1.36-2.32), and 3 month death-censored graft failure (adjusted hazard ratio, 2.0; 95% CI, 1.18-3.39), and death (adjusted hazard ratio, 3.49; 95% CI, 1.95-6.24). Patterns were similar at 12 months.Although associations may in part reflect underlying conditions, the need for midodrine before kidney transplantation is a risk marker for complications including DGF, graft failure, and death.

BACKGROUND Graft failure risk is highest during emerging adulthood (17-24 years) in kidney and heart transplant. It is unknown whether a similar association exists in liver transplant recipients. METHODS We sought to estimate the relative hazards of graft failure at different current ages, compared with those aged 21 to 24 years. We evaluated 17 181 patients recorded in the Scientific Registry of Transplant Recipients who received a first isolated liver transplant at 40 years or younger (1988-2013) and had 6 months or longer of graft function. We used time-dependent Cox models to estimate the association between current age and failure risk, defined as retransplant or death after graft failure; observation was censored at death with graft function. RESULTS There were 2540 failures. Absolute graft failure rates were highest in ages 25 to 29 years (3.0/100 person-years). Compared with individuals with the same time since transplantation, those aged 21 to 24 years had significantly higher failure rates than those younger than 17 years and older than 34 years; hazards did not differ for those aged 25 to 29 years (1.03 [0.86, 1.24]) and were lower, but not significantly, for those aged 17 to 20 years (hazards ratio, 0.83; 95% confidence interval, 0.68-1.01) and ages 30 to 34 years (hazards ratio, 0.84; 95% confidence interval, 0.70-1.01). CONCLUSIONS Among young first isolated liver transplant recipients, graft failure risks are highest in the period from 21 to 29 years of age.

BACKGROUND Descriptions of the sequelae of ABO-incompatible (ABOi) kidney transplantation are limited to single-center reports, which may lack power to detect important effects. METHODS We examined U.S. Renal Data System registry data to study associations of ABOi live-donor kidney transplantation with clinical complications in a national cohort. Among 14,041 Medicare-insured transplants in 2000 to 2007, 119 non-donor-A2 ABOi transplants were identified. A2-incompatible (n=35) transplants were categorized separately. Infection and hemorrhage events were identified by diagnosis codes on billing claims. Associations of ABO incompatibility with complications were assessed by multivariate Cox regression. RESULTS Recipients of ABOi transplants experienced significantly (P

Background Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3-dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively. Methods We prospectively tested 217 blood and 167 urine serial samples, collected monthly for 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR, MIE, or stable group (no events) in the next 30 days. Results Using absolute cutoffs and allocating to samples to AR, MIE, or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (P=0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (P=0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that, over time, serum kyn/trp ratios were higher before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008). Conclusions These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.

Background Current clinical and economic consequences of cancer after kidney transplantation are incompletely defined. Methods We examined United States Renal Data System records of Medicare-insured kidney transplant recipients in 2000 to 2011 to determine clinical and economic impacts of cancer diagnosed within the first 3 years posttransplantation. Cancer diagnoses were identified using Medicare billing codes and categorized as nonmelanoma skin cancer (NMSC), viral-linked and "other" cancers. Associations of cancers with mortality and graft loss were estimated by time-varying Cox regression. Impacts of cancer diagnoses on inpatient and outpatient costs within each year were quantified by multivariate linear regression modeling. Results Among 67 157 recipients, by 3 years posttransplant, NMSC was diagnosed in 5.7%, viral-linked cancer in 1.9%, and "other" cancers in 6.3%. Viral-linked cancer was associated with more than 3-fold increased risk in subsequent mortality until the third transplant anniversary, and nearly twice the mortality risk after year 3. "Other" cancers had similar associations with death and graft loss, whereas NMSC was associated with 33% higher mortality beyond the third year posttransplant. Viral-linked cancer had the largest inpatient and outpatient cost impacts per case, followed by "other" cancer, whereas NMSC impacted only outpatient costs. Care of new cancer diagnoses was generally more costly than care of previously established diagnoses. Cancer accounted for 3% to 5.5% of total inpatient Medicare expenditures and 1.5% to 3.3% of outpatient expenditures in the first 3 years posttransplant. Conclusions Early posttransplant malignancy is an expensive and morbid condition that warrants attention in efforts to improve pretransplant screening and management protocols before and after transplant.

Introduction. Published data for BK virus allograft nephropathy, a recently emerged graft-threatening complication of kidney transplantation, are from limited-center series. Since June 30, 2004, the Organ Procurement Transplant Network national registry in the United States started collecting data on treatment of BK virus (TBKV) on the kidney follow-up forms. This study determined the rates of TBKV within 24 months posttransplant time and elucidated the risk factors for TBKV from this multicenter database. Methods. We queried the database for all primary and solitary kidney transplant recipients transplanted between January 1, 2003 and December 31, 2006, followed through July 18, 2008, and who were reported to have TBKV. Cumulative incidence of TBKV over time was estimated using Kaplan-Meier (K-M) method to reduce potential under reporting. A Cox proportional hazards regression model was fitted to determine risk factors for TBKV development, and time dependent Cox model was fitted to determine if TBKV was associated with higher risk of graft loss. Results. We included 48,292 primary and solitary kidney transplants from the US Organ Procurement Transplant Network database. The cumulative K-M incidence of BKVAN kept rising over time (0.70% at 6 months posttransplant to 2.18% at 1 year, 3.45% at 2 years and 6.6% at 5 years). Risk for BKVAN was higher with certain immunosuppressive regimens that included rabbit antithymocyte globulin or tacrolimus/mycophenolate combinations. Higher center volume and living kidney donation exerted a protective effect. Of concern, TBKV rates were significantly higher in more recent transplant years. TBKV report was associated with higher risk of subsequent graft loss (adjusted hazard ratio= 1.69, P

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

BACKGROUND Older transplant recipients have been shown to be at greater risk for infectious death than younger adults, but no study to date has looked at relative risk of infection and infection profile differences for children versus adults, which may be very different from one another. METHODS Data from primary Medicare renal transplant recipients between 1991 and 1998 (n=64,751), as reported in the United States Renal Data System (USRDS), were analyzed for Medicare claims (both inpatient and outpatient) for infection and type of infection in the first year posttransplant. Cox regression was used to model adjusted hazard ratios (AHR) for infection. RESULTS Total infections among renal transplant recipients increased significantly in more recent years. Patients transplanted in or after 1995 had a significantly higher adjusted risk for infection compared to those transplanted earlier (AHR 1.34, 95% CI=1.29-1.39). Older adults > or = 51 years of age had the highest percentage of experiencing infection, as compared to adults between 18-50 years and children < or = 17 years (P

Limited data are available on the outcome implications of prescription narcotic use before kidney transplantation.We examined a novel database wherein national transplant registry identifiers for kidney transplant recipients were linked to records from a large U.S. pharmaceutical claims clearinghouse (2005-2010). We selected recipients with 1 year of captured pretransplant pharmaceutical fill records (N=31,197). Opioid analgesic fills in the year before transplantation were normalized to morphine equivalents (ME) and expressed as mg/kg exposures. Adjusted associations of ME level with posttransplant graft and patient survival (adjusted hazards ratio, aHR) were quantified by multivariate Cox regression.Among the 29% of the sample who filled opioid prescriptions in the year before transplantation, the 25th, 50th, and 75th percentiles of annual ME were 1.8, 5.5, and 23.7 mg/kg, respectively. Three-year graft survival was 88.0% and 84.4% in live donor recipients with upper quartiles of ME use, compared with 92.0% among those who did not receive prescription narcotics (P0.0001). Adjusted risks of posttransplant death and all-cause graft loss in live donor recipients with the highest quartile of narcotic use were 2.3 times (aHR, 2.27; 95% confidence interval, 1.66-3.10) and 1.8 times (aHR, 1.75; 95% confidence interval, 1.37-2.26), respectively, that of narcotic nonusers. Graded associations of pretransplant opioid exposure level with death and graft loss after deceased donor transplantation were also observed.Although associations may in part reflect underlying conditions or behaviors, high levels of prescription opioid use before kidney transplantation predict increased risk of posttransplant death and graft loss.

Background. Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. Methods. We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. Results. The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/ 100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 64-3048) to a median of 190 days (range 42-944). PTLD occurred with greater frequency in white children (P=0.003) and in cadaver donor transplants (P=0.019), but there was no significant predilection for gender, younger children (0-5 years), or primary diagnosis. No significant difference was found in the use of anti-T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P

Background. Angiogenesis is characteristic of chronic inflammatory reactions. The process of angiogenesis is reported to be proinflammatory in part due to enhanced adhesion events and in part due to increased perfusion and permeability to sites of inflammation. However, little is known about the association between angiogenesis and rejection. Methods. Severe combined immune deficient mice are permissive for the growth of human skin allografts and human peripheral blood mononuclear cells (PBMC). Human PBMC were injected into mice by intravenous or intraperitoneal injection. The infiltration of cells and the associated angiogenesis reactions in the skin allografts were analyzed temporally by videomicroscopy and spatially by immunohistochemistry. Results. Human alloreactive mononuclear cells migrated to human skin but not mouse skin within hours after the intravenous infusion of PBMC. Within 3 days, areas of angiogenesis were observed in the skin grafts at the sites of infiltrates. The vessel densities in skin grafts were 24±6 vessels per calibrated grid at baseline on the day of the infusion and increased to 55±16 vessels per calibrated field by day 10. Skin grafts harvested from humanized severe combined immune deficient mice 7-14 days after the intraperitoneal infusion of human PBMC showed a similar increased density of vessels that were spatially associated with mononuclear cell infiltrates. Conclusions. A significant angiogenesis response was associated with the cell infiltrates in the human skin allografts. The onset of angiogenesis appeared after the initial development of localized infiltrates and preceded the development of microvascular destruction. These findings suggest that alloreactive T cells and/or monocytes mediate the angiogenesis response in skin allografts.

Background Engineered tissues have been proposed for the treatment of a variety of conditions including the partial or complete replacement of human organs. To determine the basis for the rejection of these tissues, we analyzed the immune response to allogeneic human skin equivalent (HSE, also called Apligraf) in the humanized SCID mouse (hu-PBL-SCID). Methods Two models of hu-PBL-SCID were used for these studies. In one model, human skin or HSE was transplanted onto humanized mice so that graft survival could be analyzed. In the other model, skin grafts were allowed to heal on naive mice before humanization. This model was used to analyze the immunologic response to the vascularized skin allograft. Humanization was performed by adoptive transfer of human PBL into SCID mice by i.p. injection. Results Both human foreskin and HSE successfully engrafted onto naive SCID mice and remained stable for more than 6 months. In contrast, human foreskin was rejected by 21 days posttransplant in hu-PBL-SCID, whereas HSE consistently engrafted for more than 28 days. Treatment of HSE grafts with interferon-y for 5 days to induce maximal MHC class II molecule expression before grafting failed to induce rejection. HSE also engrafted onto hu-PBL-SCID mice that were exposed to alloantigen by prior injection with interferon-gamma-treated keratinocytes identical to those used to generate the HSE. In addition, we determined that humanization of SCID mice following engraftment and vascularization of human foreskin resulted in marked CD3+ T cell infiltrates and a lymphocyte-induced vasculitis. In contrast, the response in vascularized HSE was associated with minimal CD3+ T cell infiltration in the absence of vasculitis or morphological features of rejection. Conclusion These results support the use of HSE and other allogeneic engineered tissues in humans provided that such tissues are limited in their antigen presenting capabilities. In addition, our findings suggest a critical function for the donor endothelial cell in rejection.

On October 2005, the Organ Procurement and Transplant Network implemented a new allocation policy for kidney transplants (KTX) from deceased donors (DD) ages35 years to increase an access to transplantation from young donors for pediatric (ages18 years) recipients, which is known as Share-35 (S35). However, many of these kidneys were allocated to adult recipients. The intent of this study was to analyze the graft outcomes from S35 kidneys in pediatric and adult recipients, stratified further by recipient age, to assess if recipient age affects the outcome from these presumably ideal kidneys.The Organ Procurement and Transplant Network database from October 2005 to November 2010 involving 18,461 S35-KTX was used to calculate cumulative graft survival (CGS), death-censored graft survival, and patient survival using Kaplan-Meier estimates. The differences between survival curves were tested for significance by log-rank method after adjusting for various donor, recipient, and transplant-associated variables.With S35 implementation, children received a higher proportion of DD ages35 years. Within the pediatric age group, adolescents (ages 13-17 years) had the worst CGS. Among adults, the highest CGS was obtained in middle-aged adults, whereas young adults (ages 18-25 years) showed worse CGS. CGS in young children (ages12 years) was comparable with those in middle-aged adults. In older adults (ages55 years), CGS was lowered by higher patient death rates.Recipient age affects allograft survival from high-quality young DD kidneys, such as S35 kidneys. Best survival occurs in middle-aged adults and in children ages12 years, whereas adolescents and young adults do not derive an optimal benefit.

Posttransplant lymphoproliferative disorders (PTLDs) are associated with significant morbidity and mortality among solid-organ transplant patients, but approaches to diagnosis and management vary considerably. An international multidisciplinary panel evaluated current understanding of risk factors and classification systems and developed recommendations to aid in PTLD prevention. We considered evidence on PTLD risk factors including Epstein-Barr virus serostatus and immunosuppression and identified knowledge gaps for future research. Recommendations address prophylactic and preemptive strategies to minimize PTLD development, including modulation of immunosuppression and antiviral drug regimens. Finally, new classification criteria were outlined that may help facilitate standardized reporting and improve our understanding of PTLD.

Background Although cyclosporine use has been associated with an increased risk of new-onset gout after renal transplantation, the incidence and risk factors for new-onset gout have not been reported in the era of modern immunosuppression. Methods We conducted a retrospective cohort study of Medicare primary renal transplant patients reported in the United States Renal Data System (USRDS), using Medicare claims data to determine the incidence of new-onset gout. Cox regression analysis was used to calculate adjusted hazard ratios (AHR) for cyclosporine (including separate analysis of Neoral) compared directly with tacrolimus, for the risk of new-onset gout, adjusted for baseline demographic factors and posttransplant renal function. Results The cumulative incidence of new-onset gout was 7.6% at 3 years posttransplant. The following factors were independently associated with an increased risk of new-onset gout: use of Neoral (vs. tacrolimus, AHR 1.25, 95% CI 1.07-1.47) at discharge, recipient male sex (AHR 1.44, 95% CI 1.25-1.67), older age, higher body mass index, and more recent year of transplant. No other immunosuppressive medications were associated with new-onset gout. Diabetes was associated with a significantly lower risk of new-onset gout. The development of new-onset gout was independently associated with decreased patient survival (AHR 1.26, 95% CI 1.08-1.47) as well as death-censored graft survival. Conclusions Cyclosporine is an independent risk factor for new-onset gout after transplantation. The incidence of new-onset gout appears to be increasing even while the use of cyclosporine is decreasing, and the development of new-onset gout was an independent predictor for death and graft loss in this population.

Background Posttransplant lymphoproliferative disorders (PTLD) still represent a major preoccupation after renal transplantation, even in the most recent years. Methods We analyzed the incidence, risk, and prognostic factors of PTLD in a cohort of kidney recipients using the United States Renal Data System. Results Among 25,127 Medicare patients transplanted between 1996 and 2000, 344 developed a PTLD defined as a non-Hodgkin lymphoma (1.4%). History of pretransplant malignancy (adjusted hazard ratio [AHR]=3.54, CI 2.31-5.43), younger age (AHR=1.91, CI 1.18-3.1), fewer HLA matches (AHR=1.32, CI 1.1-1.59) and treatment by ATG (AHR=1.55, CI 1.2-1.99) and OKT3 (AHR=1.37, CI 1-1.76), especially if given for rejection therapy were associated with an increased risk of PTLD. Mycophenolate and azathioprine were associated with a lower risk of PTLD (AHR=0.6, CI 0.47-0.78 and AHR=0.66, CI 0.46-0.95, respectively). IL2-receptor inhibitors and sirolimus did not modify the risk of PTLD. Patients without induction therapy treated with tacrolimus were at greater risk of lymphoma than those treated with new formulations of cyclosporine and those treated with antimetabolites (mycophenolate and azathioprine) have a lower risk of PTLD than those without. Patients with PTLD had poor survival (64% vs. 80% at 5 years). Older age, pretransplant malignancy and OKT3 were risk factors for death whereas treatment with mycophenolate was associated with a better survival (AHR=0.49, CI=0.28-0.82). Conclusions Our study highlights the contribution of patient history and immunosuppression in the risk of PTLD in the era of modern immunosuppression.

Fischer 344 rat recipients of Lewis allografts were treated with TNP-470, a synthetic fumagillin derivative and a well-established angiogenesis inhibitor. TNP-470 alone resulted in some prolongation of graft survival as compared with untreated recipients, but all grafts ultimately failed. In contrast, treatment with cyclosporine (CsA) from day 0 to 30 resulted in prolonged graft survival and marked cardiac allograft vasculopathy (CAV) by histology (mean score 2.28+/-0.2). There were many neovessels within the intima of CAV lesions. When TNP-470 was administered in combination with CsA from day 0 to 30, the degree of CAV was similar to that with CsA alone (mean score 2.22+/-0.26). However, when TNP-470 was administered from day 30 to 120 after discontinuation of CsA, there was a marked reduction in the degree of CAV (mean score 1.08+/-0.11). Therefore, TNP-470 interrupts the progression of CAV when given late but does not prevent its development when given immediately posttransplantation.