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Univariate analyses suggest that adolescents have worse long-term allograft survival versus younger children across different SOT. This study's objective was to determine whether multivariate analyses of a large national database recording all deceased SOT (KI; LI; HR; LU) also show worse adolescent allograft survival in the different organs. Using data from the national Scientific Registry for Transplant Recipients in the USA for pediatric primary SOT from 1989 to 2010, we calculated median half-lives and constructed K-M graft survival curves. Recipient age at transplant (

Obesity is an increasingly common comorbidity at the time of kidney transplantation. Obesity is also a frequent complication of kidney transplantation. The obese transplant recipient suffers adverse metabolic and cardiovascular consequences of obesity. These metabolic and cardiovascular sequelae of obesity are major contributors to morbidity and mortality after kidney transplantation. We discuss the epidemiology and pathophysiology of obesity in the kidney transplant recipient and provide an overview of clinical studies on obesity in kidney transplantation. An approach to obesity in renal transplantation, based on the evidence to date, is presented.

Background: in previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study. Methods: we randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen. Efficacy and safety outcomes for all patients who underwent randomization and transplantation were analyzed at year 7 (month 84). Results: a total of 666 participants were randomly assigned to a study group and underwent transplantation. Of the 660 patients who were treated, 153 of the 219 patients treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen were followed for the full 84-month period; all available data were used in the analysis. A 43% reduction in the risk of death or graft loss was observed for both the more-intensive and the less-intensive belatacept regimens as compared with the cyclosporine regimen (hazard ratio with the more-intensive regimen, 0.57; 95% confidence interval [CI], 0.35 to 0.95; P=0.02; hazard ratio with the less-intensive regimen, 0.57; 95% CI, 0.35 to 0.94; P=0.02), with equal contributions from the lower rates of death and graft loss. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but declined with the cyclosporine regimen. The cumulative frequencies of serious adverse events at month 84 were similar across treatment groups. Conclusions: seven years after transplantation, patient and graft survival and the mean eGFR were significantly higher with belatacept (both the more-intensive regimen and the less-intensive regimen) than with cyclosporine. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00256750).

Summary Objectives The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients. Methods Cases of proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance ® ) registry – a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 – were analyzed with respect to clinical outcome. Results Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy ( n =464 [48.3%]). Two hundred and eighty patients (29.2%) received solid organ transplant; 268 patients (27.9%) underwent hematopoietic stem cell transplantation. Identified isolates included Aspergillus fumigatus (72.6%), Aspergillus flavus (9.9%), Aspergillus niger (8.7%) and Aspergillus terreus (4.3%). The lung was most frequently affected. Following diagnosis, 47% patients received monotherapy – voriconazole (70%), an amphotericin B formulation (13.8%), or an echinocandin (10.5%) – while 279 patients (29%) received combination therapy. Twelve-week overall survival was 64.4%. Conclusions In this series of patients with IA, the lung was the predominant focus of infection, A. fumigatus was the major species isolated, and overall survival appeared slightly improved compared with previous reports.

Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS. We stratified on basis of cold ischemic time (CIT) to determine the interaction of preservation techniques, CIT and DCD kidneys on developing DGF. Of 54 136 recipients, 4923 received DCD kidneys of which 3330 (67%) underwent PP. Of 49 213 DBD recipients, 7531 (15%) underwent PP. DCD had a higher risk of DGF versus DBD (adjusted odds ratio, AOR 3.2; 3.0-3.5). PP kidneys had less DGF (AOR 0.59; 0.56-0.63) compared to CS. Interaction models of method by donor type referenced to PP/DBD revealed CS/DBD kidneys had higher DGF (AOR 1.8; 1.7-1.9), whereas CS/DCD kidneys had the highest risk of DGF (AOR 5.01; 4.43-5.67). Even though suggestive for a benefit of PP on DGF, this retrospective analysis cannot address whether this is an intrinsic effect of PP or is associated with the logistics of PP such as discard of DCD kidneys based on pump parameters.

The Prospective Antifungal Therapy Alliance (PATH Alliance®) performed prospective surveillance of invasive fungal infections (IFIs) among patients hospitalized at 25 medical centers in North America between 2004 and 2008, collecting information on the epidemiology, diagnosis, treatment, and mortality rates of IFIs. In total, 7526 IFIs were identified in 6845 patients. Candida spp. (73.4%) were the most common pathogens, followed by Aspergillus spp. (13.3%), and other yeasts (6.2%). Culture was the most frequently used diagnostic test in the majority of IFI categories. Most patients with invasive candidiasis were treated with fluconazole (48.3%) and the echinocandins (34.0%), while voriconazole (45.5%) was the main antifungal agent for invasive aspergillosis. The 12-week survival rate ranged from 37.5% for hematopoietic stem cell transplant recipients to ~75.0% for those with HIV/AIDS. In summary, the findings of the PATH Alliance® registry provide a better understanding of the epidemiology of a vast variety and large numbers of IFIs.

In a prior multiorgan transplant database study, recipient Epstein-Barr virus (EBV) seronegativity was not associated with increased risk for posttransplant lymphoproliferative disorders (PTLD) in liver transplants (LTX), at variance with prior single center reports and with data from kidney and heart transplants (KTX and HTX). The Scientific Registry of Transplant Recipients (SRTR) in the United States is the only other registry with data on the required variables for comparison.Our study set comprised 112 756 KTX (580 PTLDs; 0.51%), 13 937 HTX (140 PTLDs; 1.0%) and 40 437 LTX (383 PTLDs; 0.95%) performed January 2003 onward. The unadjusted hazard ratio (HR) for PTLD if recipient EBV seronegative was 5.005 for KTX, 6.528 for HTX and 2.615 for LTX (p < 0.001 for all). In models adjusted for multiple covariates, the adjusted HR was 3.583 (p < 0.001) for KTX, 4.037 (p < 0.001) for HTX, 1.479 (p = 0.03) for LTX. Interaction models using EBV seropositive KTX as reference group showed significantly higher risk for all other EBV seronegative organ transplant groups and also for EBV seropositive LTX (AHR 2.053, p < 0.0001).Recipient EBV seronegativity is still significantly associated with risk for PTLD in LTX, though less so because of higher baseline risk in the EBV seropositive LTX group.

Summary Background and objectives Many factors have been shown to be associated with ESRD patient placement on the waiting list and receipt of kidney transplantation. Our study aim was to evaluate factors and assess the interplay of patient characteristics associated with progression to transplantation in a large cohort of referred patients from a single institution. Design, setting, participants, & measurements We examined 3029 consecutive adult patients referred for transplantation from 2003 to 2008. Uni- and multivariable logistic models were used to assess factors associated with progress to transplantation including receipt of evaluations, waiting list placement, and receipt of a transplant. Results A total of 56%, 27%, and 17% of referred patients were evaluated, were placed on the waiting list, and received a transplant over the study period, respectively. Older age, lower median income, and noncommercial insurance were associated with decreased likelihood to ascend steps to receive a transplant. There was no difference in the proportion of evaluations between African Americans (57%) and Caucasians (56%). Age-adjusted differences in waiting list placement by race were attenuated with further adjustment for income and insurance. There was no difference in the likelihood of waiting list placement between African Americans and Caucasians with commercial insurance. Conclusions Race/ethnicity, age, insurance status, and income are predominant factors associated with patient progress to transplantation. Disparities by race/ethnicity may be largely explained by insurance status and income, potentially suggesting that variable insurance coverage exacerbates disparities in access to transplantation in the ESRD population, despite Medicare entitlement. Clin J Am Soc Nephrol 6: 1760–1767, 2011. doi: 10.2215/CJN.08620910

Organ survival in the short-term period post-transplant has improved dramatically over the past few decades. Whether this has translated to a long-term survival benefit remains unclear. This study quantifies the progression of nonrenal solid organ transplant outcomes from 1989 to 2009 in liver, lung, heart, intestine and pancreas transplants. Long-term graft survival was analyzed using data on adult solid organ transplant recipients from the UNOS/SRTR database and is reported as organ half-life and yearly attrition rates. Liver, lung, heart, intestine and pancreas half-lives have improved from 5.8 to 8.5, 1.7 to 5.2, 8.8 to 11, 2.1 to 3.6 and 10.5 to 16.7 years, respectively. Long-term attrition rates have not shown the same consistent improvement, with the yearly attrition rate 5-10 years post-transplant for liver, lung, heart and pancreas changing from 4.7 to 4.3, 10.9 to 10.1, 6.4 to 5.1 and 3.3 to 4.2, respectively. Attrition rates for intestine and pancreas transplantation alone display more variability due to smaller sample size but exhibit similar trends of improved first-year attrition and relatively stagnant long-term attrition rates. With first-year survival and attrition rates almost at a pinnacle, further progress in long-term survival will come from targeting endpoints beyond first-year rejection and survival rates.

The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation. Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm. The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm. This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded. (Less)

BACKGROUND: Despite evidence of favorable long-term effects of mycophenolate mofetil (MMF) in renal transplantation, its introduction at different times posttransplant has not been studied in large cohorts. METHODS: Single-organ renal allograft recipients (n=2217) who had MMF introduced 6 months to more than 20 years posttransplantation for various reasons were included in TranCept Switch, a multicenter, noninterventional, observational 4-year study. Changes in renal function before and after the introduction of MMF were analyzed. RESULTS: MMF was introduced because of renal function decline in 43% of patients and poor tolerability with previous treatment in 23% of patients. The change in slope of the calculated glomerular filtration rate (modification of diet in renal diseases formula) regression line before and after MMF initiation was +2.01 mL/min per year (P

Graft failure is a major cause of broad sensitization but it is not clear whether sensitization occurs immediately after transplant loss or other factors (transfusions, nephrectomy, etc.) trigger it subsequently. Human leukocyte antigen antibodies were measured in 104 patients who lost a kidney transplant. The overall frequency of sensitization was 70%, with a similar rate in patients who lost the graft within 3 days. However, 81% of the patients did not have antibodies at the time of graft loss. Many patients underwent graft nephrectomy, had transfusions, and discontinued immunosuppression, obscuring possible individual effects of each factor. However, some patients without nephrectomy or transfusions made antibodies, whereas none of the patients continuing with immunosuppression did. The results suggest that some patients, such as those with live donors or otherwise candidates for prompt retransplantation, may benefit from continuing maintenance immunosuppression as a means of preventing sensitization after graft loss.

Renal allograft survival has increased tremendously over past decades; this has been mostly attributed to improvements in first-year survival. This report describes the evolution of renal allograft survival in the United States where a total of 252 910 patients received a single-organ kidney transplant between 1989 and 2009. Half-lives were obtained from the Kaplan-Meier and Cox models. Graft half-life for deceased-donor transplants was 6.6 years in 1989, increased to 8 years in 1995, then after the year 2000 further increased to 8.8 years by 2005. More significant improvements were made in higher risk transplants like ECD recipients where the half-lives increased from 3 years in 1989 to 6.4 years in 2005. In low-risk populations like living-donor-recipients half-life did not change with 11.4 years in 1989 and 11.9 years in 2005. First-year attrition rates show dramatic improvements across all subgroups; however, attrition rates beyond the first year show only small improvements and are somewhat more evident in black recipients. The significant progress that has occurred over the last two decades in renal transplantation is mostly driven by improvements in short-term graft survival but long-term attrition is slowly improving and could lead to bigger advances in the future.

The objective of the present study was to determine if there are changes on complement (C) activation and concentration of HLA antibodies (Abs) in patients treated with intravenous immunoglobulin (IVIG). The patients evaluated were given IVIG as treatment of Ab-mediated rejection or desensitization. The patients' sera obtained before and after IVIG administration were tested for their effects on the deposition of both IgG (HLA Abs) and C3b (C activation) as measured by flow cytometry on T cells. IVIG consistently inhibited C activation when measured shortly after IVIG infusion but returned to the initial levels at 2-4 weeks, when total serum IgG also returned to pre-infusion levels. C inhibition was more pronounced with higher IVIG doses and the degree of inhibition was inversely proportional to the HLA Ab concentrations. IVIG did not block the binding of HLA Abs immediately after administration, although levels were slightly but consistently lower after several monthly IVIG infusions. The data show that C inhibition by IVIG is short-lived and that IVIG induces only a mild reduction of HLA Abs, seen not immediately but after months of treatment. These results may explain the inconsistent results of IVIG to achieve desensitization.

OBJECTIVE: To compare length of stay, readmissions, infections, and mortality in patients with end-stage renal disease who have been admitted to receive renal transplant, stratified according to diabetes status and admission glucose concentration. METHODS: We conducted a retrospective analysis of all adult patients who underwent renal transplant at an academic center during 2006. Patients were stratified according to diabetes status before transplant and glucose concentration at hospital admission (hyperglycemic [> 180 mg/dL] or normoglycemic [≤ = 180 mg/dL]). The groups were compared with respect to length of stay, number of readmissions during the 2-year period after transplant, infections, and mortality. RESULTS: Ninety-eight patients underwent renal transplant during the study period, and 11 were excluded because of incomplete data. Thus, 87 patients were included. There was a trend towards greater length of stay and higher mortality in patients with known diagnosis of diabetes. When stratified according to glucose concentration at admission, patients with hyperglycemia had a significantly longer length of stay than normoglycemic patients (10 ± 4.3 days vs 7.9 ± 2.9; P = .039), even after correcting for diabetes status. CONCLUSION: Hyperglycemia at hospital admission, rather than a known diagnosis of diabetes, is associated with increased length of stay in patients admitted for renal transplant.

Posttransplant erythrocytosis (PTE) poses a potential risk of thrombosis in kidney transplantation. Clinical observation of our systemically drained simultaneous kidney pancreas transplant (S-SPK) patients showed a higher incidence of PTE and need for phlebotomies. To evaluate the incidence of PTE we analyzed hematocrit (Hct) levels and frequency of phlebotomies in 94 SPK as compared to 174 living donor (LD) recipients and 53 type-I diabetic with kidney transplant only. For study purposes we defined PTE as Hct >50% or the necessity for phlebotomies. Kaplan-Meier plots and Cox proportional hazard models were used to examine the association between the transplant type and PTE. We found an increased incidence of PTE in SPK compared to LD (p < 0.001). In the multivariate model, SPK had a 5-fold risk for the development of PTE (AHR 5.3, 95% CI 1.8, 15.9). The incidence of therapeutic phlebotomy was 13% among SPK patients and 4% in LD kidney recipients; 19 patients altogether. A total of 64 units were phlebotomized (48-SPK and 16-LD). Type I diabetic patients with a kidney transplant showed a 0% incidence of PTE. We observed a greater incidence of PTE and phlebotomies in S-SPK compared to LD with kidney only transplant recipients.

Transplant nephrectomy improves survival following a failed renal allograft. J Am Soc Nephrol 21: 324–380, 2010 {#article-title-2} 169 170 There is a lack of consensus among transplant physicians regarding the optimal management of the large number of patients who return to dialysis (approximately 2000 per year) with a failed kidney transplant (1–3). The high rate of morbidity and mortality experienced by patients after primary kidney transplant failure exceeds those observed in dialysis patients who are awaiting kidney transplantation (4–7). Dialysis patients with failed previous transplants have been shown to have a standardized mortality ratio of 1.35 compared with dialysis patients who have never received a renal transplant (8). Several predictors of patient survival after allograft failure have been identified, such as age, diabetes, HLA matching, gender, and first transplant donor type (1,9). Mortality after primary allograft failure is strongly influenced by the type of ESRD, the highest rate found among patients with type 1 diabetes compared with either type 2 diabetes or other causes of ESRD (1). The reasons for the poor survival after graft failure have remained elusive. The triggering of an inflammatory process by the retained allograft (characterized by hypoalbuminemia, erythropoietin resistance, high ferritin, and elevated C-reactive protein) and an increased incidence of infectious and cardiac complications as a result of ongoing immunosuppression have been observed but not yet confirmed by controlled clinical studies (10–12). The goal of this observational study was to evaluate the impact of transplant nephrectomy on the survival of patients who return to dialysis after kidney transplant failure. Using the US Renal Data System, the authors identified and analyzed a cohort of patients ( n = 10,951) who returned to dialysis (hemodialysis and peritoneal dialysis) during a 10-year period spanning from January 1994 through December 2004. #### Findings. Thirty-one percent ( n = 3451) of the study cohort underwent a transplant nephrectomy during the study period. …

Background and objectives: Uric acid (UA) has been linked to renal damage in experimental models of kidney failure. In humans, no definitive link between UA and renal function has been established, but several epidemiologic studies have suggested that higher UA levels are associated with accelerated loss of renal function, higher incidence of dialysis, and death. Many of the associations have been limited by the colinearity between UA levels and renal function. Renal transplantation is no exception, and limited information is available concerning the independent role of UA on progression of renal function in transplant recipients. Design, setting, participants, & measurements: We investigated the association between UA and renal function progression during the first 3 yr after transplantation, adjusted for baseline renal function, in 1645 patients who were enrolled in the Symphony study. Results: When corrected for baseline renal function, UA levels 1 mo after transplantation were not associated with 3-yr renal function (P = 0.62). There was a strong colinearity between calculated renal function and UA levels 1 mo after transplantation. In fact, when not corrected for baseline renal function, there was a significant association between UA and renal function at 3 yr (P = 0.005). Conclusions: Low renal function is associated with higher UA levels, but higher UA levels are not independently associated with progression of renal dysfunction after kidney transplantation.

Background and objectives: Waiting times to deceased-donor transplantation (DDTx) have significantly increased in the past decade. This trend particularly affects older candidates given a high mortality rate on dialysis. Design, setting, participants, & measurements: We conducted a retrospective analysis from the national Scientific Registry of Transplant Recipients database that included 54,669 candidates who were older than 60 yr and listed in the United States for a solitary kidney transplant from 1995 through 2007. Using survival models, we estimated time to DDTx and mortality after candidate listing with and without patients initially listed as temporarily inactive (status 7). Results: Almost half (46%) of candidates who were older than 60 yr and listed in 2006 through 2007 are projected to die before receiving a DDTx. This proportion varied by individual characteristics: Diabetes (61%), age ≥70 yr (52%), black (62%), blood types O (60%) and B (71%), highly sensitized (68%), and on dialysis at listing (53%). Marked variation also existed by United Network for Organ Sharing region (6 to 81%). The overall projected proportion was reduced to 35% excluding patients who initially were listed as status 7. Conclusions: These data highlight the prominent and growing challenge facing the field of kidney transplantation. Older candidates are now at significant risk for not surviving the interval in which a deceased-donor transplant would become available. Importantly, this risk is variable within this population, and specific information should be disseminated to patients and caregivers to facilitate informed decision-making and potential incentives to seek living donors.

There has been a notable rise of BK virus among kidney transplant recipients. Single-center reports have identified risk factors for development of BK virus. However, there has not been an assessment of risk factors and incidence of this complication at a national level. This study utilized newly collected follow-up information from the national SRTR database to investigate incidence, risk factors and outcomes for solitary kidney transplant recipients associated with treatment for BK virus (TBKV) from 2004 to 2006. Logistic and Cox models were utilized to assess risk factors and evaluate graft survival associated with TBKV. Incidence of TBKV was 1.6% at 6 months and 2.6% at 1 year following transplantation. Patients with and without TBKV at 6 months had 79% and 90% 3-year overall graft survival respectively. Risk factors included advanced donor age, pediatric, African American and male recipients, human leukocyte antigen-mismatching and tacrolimus and thymoglobulin induction as baseline immunosuppression. Acute rejection episodes were more frequent prior to and following TBKV. TBKV is a common and rising incidence, varies based on transplant characteristics and should be included as a safety endpoint in studies investigating immunosuppressive protocols. Careful monitoring and further understanding of disease etiology and treatment strategies are needed.

Background. Human leukocyte antigen (HLA) antibodies produced after transplantation are frequently measured in transplant recipients, because they are strongly associated with humoral rejection and graft loss. However, antibodies can be induced by posttransplant blood transfusions rather than by the graft, casting doubts about the possible role of antibodies in a patient with graft dysfunction. Methods. We recorded the posttransplant transfusions in 746 patients transplanted during a 6-year period. Rejection episodes were evaluated after exclusion of patients who were transfused proximate to the time of rejection. Specimens for solid-phase HLA antibody testing were available in 199 patients. Results. The frequency of transfusions was 45%, but it was higher in deceased donor transplants (51%) than in live donor transplants (30%). Almost 80% of the transfusions were given during the first month after transplant. However, the incidence of posttransplant antibodies was similar in patients transfused and not transfused, and only 1 of 12 patients who received more than 10 transfusions produced antibodies. There was no evidence that posttransplant antibodies not directed to donor antigens were triggered by transfusions. The incidence of rejection episodes, allograft nephropathy, and graft loss was slightly more in transfused patients but the differences were not statistically significant. Conclusions. When HLA antibodies are detected posttransplant, they are likely induced by the graft rather than by any transfusions the patient may have received. The results suggest that posttransplant transfusions do not have the sensitizing or down-regulatory effects of pretransplant transfusions.

There are currently over half a million end-stage renal disease patients and70,000 patients listed to receive a deceased donor kidney transplant in the United States. To receive a deceased donor transplant, patients are placed on a waiting list at one of approximately 240 centers. Although candidate decisions to list at a particular center may often be made passively (based on proximity or physician referral), the important question remains as to whether the center of listing has a significant impact on patient outcomes.The study evaluated adult kidney transplant candidates in the United States listed from 1995 to 2000 (n = 108,928) with follow-up through 2006. The primary outcome of patient survival was investigated with survival models evaluated with respect to 4 center characteristics (volume, donor quality, waiting time, past performance). Center characteristics derived from years preceding listing, simulating information that could be attainable for prospective candidates.Center waiting time had a marked association with survival (Adjusted hazard ratio = 1.32, 95% confidence interval: 1.27-1.38 for the longest waiting times). Past performance and donor quality also had significant association with survival; center volume was not a significant factor. The cumulative impact of center factors resulted in an average 4-year difference in life expectancy. Center characteristics at listing were strongly correlated with levels at the time of transplantation and centers with the "best" characteristics were located in every region of the country.Center characteristics have significant impact on kidney transplant candidate survival. Information regarding the variability and importance of center factors should be clearly disseminated to transplant candidates.

Natural killer cells are known to have anti-tumor activity in haploidentical hematopoietic stem cell transplantation. We hypothesized that reconstituted circulating natural killer cells may be associated with improved relapse-free survival after HLA-matched hematopoietic stem cell transplantation.Serial peripheral blood absolute natural killer cell counts were prospectively measured by flow cytometry of lymphocytes expressing CD56 and CD16 in 167 patients. Cluster analysis was used at engraftment and 60 days post-transplant to distinguish patients with high and low absolute natural killer cell counts. At engraftment 80 patients had high counts (22.2/mm3) and 43 had low counts. At 60 days post-transplant 84 patients had high counts (18.2/mm3) and 38 had low counts. The primary study end-points were death, relapse and acute graft-versus-host disease. The median follow-up was 373 days (range, 67-1767).Among patients given reduced intensity conditioning, a low absolute natural killer cell count at 60 days post-transplant was independently associated with relapse [adjusted hazard ratio (AHR) = 28.4, 95% confidence interval (CI) 4.3-186.4] and death (AHR = 17.5, 95% CI 4.3-71.3). Furthermore, patients given reduced intensity conditioning who had a high absolute natural killer cell count at 60 days had a significantly better 1-year survival than those with a low count by Kaplan-Meier analysis (83% vs. 11%, p0.001). Multivariate analysis confirmed that low 60-day absolute natural killer count in patients given reduced intensity conditioning was independently associated with an increase in relapse or death (AHR = 20.22, 95% CI 4.76-85.40). In contrast, there was no significant association between 60-day absolute natural killer cell counts and clinical outcomes in patients receiving myeloablative conditioning. There was no significant association between absolute natural killer cell count and graft-versus-host disease.High natural killer cell reconstitution is associated with reduced relapse and death without an increased incidence of graft-versus-host-disease after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Measuring reconstituted natural killer cells expressing CD56(+)/CD16(+) post-transplant may have novel prognostic and therapeutic implications.

Exceptionally low acute rejection rates and excellent graft survival can be achieved with cyclosporine and tacrolimus (CNI)-based immunosuppressive protocols that incorporate antiproliferative immunosuppressants and corticosteroids. However, despite short-term success, long-term attrition of graft function and side effects of immunosuppressive agents continue to be significant problems, leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may contribute to long-term damage in transplant kidneys. Metabolic, cosmetic, and neuropsychiatric complications of steroids affect quality of life after transplantation. Newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs or steroids altogether. In this report we review studies that address either CNI or steroid minimization strategies and discuss their risks versus benefits. Given the accumulated experience to date, in our opinion the use of CNIs and steroids as part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI and steroid minimization strategies needs to be further validated in controlled clinical trials with adequate long-term follow-up.

Timely access to transplantation for eligible patients with end-stage renal disease (ESRD) is critical. However, pressures exist to improve efficiencies in transplantation and to achieve high center performance ratings, including the recently submitted "Final Rule" by Center for Medicare and Medicaid Services. This policy may affect the availability of public funding for as many as 10% of kidney transplant centers in the United States. This study examined adult solitary kidney transplant candidates from 1995 to 2005 using a national database. Mortality rates were calculated for candidates at individual centers prior to transplantation. Posttransplant survival and center's standardized mortality ratios were then calculated and compared to rates of candidate mortality. Candidate mortality rates varied substantially across centers (highest quartile with almost 2-fold elevated mortality). Recipients at centers with the highest candidate mortality rates had approximately 1.9 years reduced median graft survival for deceased donor transplants and decreased patient survival even after risk adjustment (adjusted hazard ratio=1.33, 95% confidence interval 1.25-1.41). This association was greater among living transplants (adjusted hazard ratio=1.49, 95% confidence interval 1.31-1.70). For 1-year outcomes, 19% (43/224) of centers met criteria for low performance for either graft loss or patient death in living or deceased donor transplants. Of these, 51% were among centers with the highest candidate mortality as compared to 7% of centers with the lowest candidate mortality. The health status of centers' transplant candidate pool is a significant determinant of outcomes and performance ratings. Centers with a higher risk candidate pool are significantly more likely to be identified for poor performance and could potentially lose public funding. Pressures to enhance outcomes may lead centers to exclude high-risk but otherwise viable transplant candidates.

The survival advantage of kidney transplantation extends to many high-risk ESRD patients; however, numerous factors ultimately determine which patients are evaluated and listed for the procedure. Broad goals of patient evaluation comprise identifying patients who will benefit from transplantation and excluding patients who might be placed at risk. There is limited data detailing whether current access limitations and screening strategies have achieved the goal of listing the most appropriate patients. The study estimated the life expectancy of adult patients in the United States prior to transplantation with ESRD onset from 1995 to 2003. Factors associated with transplant listing were examined based on patient prognosis after ESRD. Approximately one-third of patients listed for transplantation within 1 year of ESRD had/=5-year life expectancy on dialysis. In contrast, one-third of patients not listed had5-year life expectancy. The number of patients not listed with 'good' prognosis was significantly higher than those listed with 'poor' prognosis (134 382 vs. 16 807, respectively). Age, race, gender, insurance coverage and body mass index (BMI) were associated with likelihood for listing with 'poor' prognosis and not listing with 'good' prognosis. Over the past decade, many ESRD patients viable for transplantation have not listed for transplantation while higher-risk patients have listed rapidly.

The introduction of several immunosuppressive agents over the past decade has reduced the rate of acute rejection significantly and has improved short-term renal allograft survival. However, their impact on long-term outcomes remains unclear. Current immunosuppressive strategies are focused on improving long-term graft and patient survival along with maintaining allograft function. The approval of the new immunosuppressive agents: rabbit antithymocyte globulin, basiliximab, daclizumab, tacrolimus, mycophenolate, and sirolimus, also has facilitated the development of steroid- and calcineurin inhibitor-sparing regimens in kidney transplantation. We discuss the impact of various immunosuppressive regimens on the outcome measures of kidney transplantation: acute rejection episodes, allograft survival, and renal function.

Patient and graft survival following renal transplantation have improved markedly over the past decade, meaning that physician attention has turned more towards minimizing short- and long-term toxicities associated with immunosuppressive regimens. Gastrointestinal (GI) adverse events are common following renal transplantation and all immunosuppressive regimens have been associated with such events. Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) are potential components of immunosuppression regimens, and are associated with the most successful outcomes in kidney transplantation. The effects of MMF and EC-MPS are likely mediated via the active metabolite mycophenolic acid (MPA). The GI events caused by both MMF and EC-MPS may, in part, be related to MPA, independent of the formulation or route of administration. MPA may produce GI events either through direct action or through the action of it metabolites. However, many other factors may cause GI events observed following renal transplantation. These include the surgery itself and concurrent diseases such as diabetes, and bacterial, viral, fungal and parasitical infections. Additionally, numerous concomitant non-immunosuppressive agents, including antibiotics hypoglycaemic and proton-pump inhibitors, can be associated with GI events. In a recent trial in renal transplant patients with severe diarrhoea, approximately 50% of patients achieved resolution of diarrhoea through methods other than altering their immunosuppressive regimens. Indeed altering of the immunosuppressive regimen may lead to the risk of acute rejection. Thus, in order to reduce the risk of rejection and subsequent damage to the graft, it is important to consider other causes of GI events in renal transplant patients before altering immunosuppressive regimens.

We evaluated outcomes with the sirolimus (SRL) and mycophenolate mofetil (MMF) combination regimen (SRL/MMF) in solitary kidney transplant recipients transplanted between 2000 and 2005 reported to the Scientific Registry of Renal Transplant Recipients. Three-and-a-half percent received SRL/MMF (n = 2040). Six-month acute rejection rates were higher with SRL/MMF (SRL/MMF: 16.0% vs. other regimens: 11.2%, p < 0.001). Overall graft survival was significantly lower on SRL/MMF. SRL/MMF was associated with twice the hazard for graft loss (AHR = 2.0, 95% C.I., 1.8, 2.2) relative to TAC/MMF, also consistent in both living donor transplants (AHR = 2.4, 95% C.I., 1.9, 2.9) and expanded criteria donor transplants (AHR = 2.1, 95% C.I., 1.7-2.5). Among deceased donor transplants, DGF rates were higher in the SRL/MMF cohort (47% vs. 27%, p < 0.001). However, adjusted graft survival was also significantly inferior with SRL/MMF in DGF-free patients (AHR = 1.9, 95% C.I., 1.6-2.3). In analyses restricted to patients who remained on the discharge regimen at 6 months posttransplant, conditional graft survival in deceased donor transplants was significantly lower with SRL/MMF compared to patients on TAC/MMF or CsA/MMF regimens at 5 years posttransplant (64%, 78%, 78%, respectively, p = 0.001) and across all patient subgroups. In conclusion, SRL/MMF is associated with inferior renal transplant outcomes compared with other commonly used regimens.

Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C(2)) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C(2) maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction.In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C(2) range) or group B (lower-C(2) range).Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA35% or4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients.Low cyclosporine C(2) levels are associated with improved renal function compared with higher C(2) levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C(2) levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients.

Improvements across many facets of transplantation have led to better 1-yr outcomes of transplanted organs. In this study, we assessed whether longer-term attrition rates improved in pediatric kidney (KI), liver (LI), heart (HR) and lung (LU) transplant (TX) survival. We analyzed data between 1989 and 2008 from 5747 KI, 7348 LI, 5103 HR, and 715 LU TXs (under 18 yr of age at transplant, first solitary transplant only), from the National Scientific Registry of Transplant Recipients database in the USA. Kaplan-Meier (K-M) or ordinary least square (OLS) estimates were used to calculate median and projected survival half-lives. Attrition rates, defined as percent failing within a given time period, were stratified by year of TX. Median half-lives from 1989 TX year to 2005 TX year have shown a major improvement only in LI TX, remaining unchanged in HR and KI TX, or remaining very low in LU TX. All four organ TX types have shown a dramatic drop in first-year attrition rates from 1989 to 2008. However, longer-term attrition rates (1-3, 3-5, 5-10 yr) have remained largely unchanged for all four organ TX types. Further progress in long-term survival will need targeting end-points beyond first-year rejection and survival rates.

The toxicity of standard triple-therapy immunosuppressive regimens has been identified as a possible factor in the failure to extend long-term renal allograft survival despite a continued decline of acute rejection rates. The result has been increasing focus on the use of mycophenolate mofetil-based, low-toxicity immunosuppressive regimens, which have been shown in randomized studies to have the potential to improve long-term graft survival. This Clinical Update discusses the likely risks and benefits for switching the immunosuppressive regimen in clinical practice.

Over the last 10 years, there have been important changes in immunosuppression management and strategies for solid-organ transplantation, characterized by the use of new immunosuppressive agents and regimens. An organ-by-organ review of OPTN/SRTR data showed several important trends in immunosuppression practice. There is an increasing trend toward the use of induction therapy with antibodies, which was used for most kidney, pancreas after kidney (PAK), simultaneous pancreas-kidney (SPK) and pancreas transplant alone (PTA) recipients in 2004 (72-81%) and for approximately half of all intestine, heart and lung recipients. The highest usage of the tacrolimus/mycophenolate mofetil combination as discharge regimen was reported for SPK (72%) and PAK (64%) recipients. Maintenance of the original discharge regimen through the first 3 years following transplantation varied significantly by organ and drug. The usage of calcineurin inhibitors for maintenance therapy was characterized by a clear transition from cyclosporine to tacrolimus. Corticosteroids were administered to the majority of patients; however, steroid-avoidance and steroid-withdrawal protocols have become increasingly common. The percentage of patients treated for acute rejection during the first year following transplantation has continued to decline, reaching 13% for those who received a kidney in 2003, 48% of which cases were treated with antibodies.

Cinacalcet, a calcimimetic, was evaluated in persistent hyperparathyroidism after kidney transplantation (Tx). Ten kidney transplant recipients and one kidney-pancreas recipient with persistent post-Tx hypercalcemia (serum calcium [SCa] > 10.2 mg/dl), stable graft function, and intact parathyroid hormone (iPTH) > or = 2 times normal received 30 mg/d cinacalcet between 2 mo and 5 yr after Tx. SCa, serum phosphorus (SP), and iPTH were measured before and after cinacalcet. Mean pre-cinacalcet SCa was 10.9 mg/dl (8.6 to 11.9 mg/dl). Average pre-cinacalcet SP was 2.9 mg/dl (1.8 to 4.0 mg/dl). Mean pre-cinacalcet iPTH was 267.0 pg/ml (99 to 723 pg/ml). After cinacalcet, SCa decreased on average by 1.6 mg/dl (95% confidence interval 1.2 to 2.1; P < 0.0001). Post-cinacalcet SP increased on average 0.45 mg/dl (P = 0.046). Post-cinacalcet iPTH averaged 156.9 mg/dl (P = 0.10). Graft function remained stable. Cinacalcet lowers SCa and raises SP in the short term in patients with persistent post-Tx hyperparathyroidism; long-term bone effects and persistent hyperparathyroidism merit further study.

Purpose of reviewPancreas transplantation after kidney transplantation improves the quality of life of kidney transplant recipients by removing the exogenous need for insulin and decreasing the number of hypoglycemic events. Recent studies have raised concern, however, over the potential negative im

BK virus nephropathy (BKVN) is now recognized as a major cause of renal allograft loss. Recent reports suggest that retransplantation in patients with graft loss due to BKVN is safe after return to dialysis. Since early transplantation is associated with improved outcomes, it would be advantageous if this procedure could be performed prior to ultimate graft loss. However, little data are available regarding the safety of this approach during active viremia. In this report, we describe successful preemptive retransplantation with simultaneous allograft nephrectomy in two patients with active BKVN and viremia at the time of surgery. With 21- and 12-month follow-up, respectively, both patients have stable allograft function and no evidence for active viral replication. We conclude that preemptive retransplantation can be considered in patients with failing allografts due to BKVN.

Interleukin (IL)–12 has antitumor effects in murine studies. To evaluate this clinically, we investigated whether high levels of circulating IL-12 in patients after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with improved relapse-free survival. We prospectively studied 134 patients undergoing HSCT. Median follow-up was 1158 days (range, 70-1792 days). Plasma IL-12 levels were measured before transplantation and on days 0, +4, +7, and +14 after transplantation. The highest levels were seen on days +4 and +7 and were categorized by a cluster analysis of the logarithmically transformed IL-12 concentrations, which were then correlated with relapse-free survival. Forty-six patients had low levels of IL-12 (median, 2 pg/mL; range, 0-6.5 pg/mL), 49 patients had medium levels (median, 20.5 pg/mL; range, 7-75.5 pg/mL), and 25 patients had high levels (median, 181 pg/mL; range, 84-623 pg/mL). Patients with high IL-12 levels before transplantation had the highest increase after transplantation. With a multivariate Cox model for relapse onset, with the low IL-12 level as the reference, patients in the high–IL-12 group had an adjusted hazard ratio of 0.27 (95% confidence interval, 0.09-0.79), and medium group patients had a hazard ratio of 0.65 (95% confidence interval, 0.31-1.36). The incidences of relapse at 500 days by Kaplan-Meier analysis by IL-12 group were 23.0% (high group), 40.3% (medium group), and 48.8% (low group). There was no association between IL-12 levels and the risk of acute graft-versus-host disease (GVHD; P = .51) or chronic GVHD (P = .28). In conclusion, high IL-12 levels after HSCT are associated with improved relapse-free survival without increasing the risk for GVHD. Patients with high pretransplantation IL-12 levels have an increased likelihood of higher posttransplantation IL-12 levels, possibly because of a host-graft interaction, and this may predispose to better clinical outcomes.

Dialysis is the most common therapeutic intervention for patients with end-stage renal disease (ESRD). The demonstration of a clear survival benefit associated with renal transplantation has made it the preferred treatment option for ESRD patients medically cleared for transplant. This has invoked a shift in thinking regarding the timing of transplantation. Impaired renal function and particularly ESRD with dialysis are significant cardiovascular risk factors for this population. Part of these cumulative effects can probably be avoided by transplantation without prior dialysis. In fact, the evidence to date demonstrates a significant advantage for allograft and patient survival associated with preemptive transplantation. In addition, preemptive transplantation is associated with better quality of life for these patients and is less costly than dialysis. The key for patients approaching ESRD is early referral to a transplant center to explore the most appropriate treatment options in a timely fashion. In fact, it is better to transplant patients preemptively than to wait until they reach ESRD and start dialysis.

Mycophenolate mofetil (MMF) has been used in kidney and pancreas transplantation for almost 10 years. In the pivotal phase III trials, MMF use was accompanied by a dramatic reduction of rejection rates in kidney transplantation; however, the impact on graft and patient was undetermined. Analyses of the United States Renal Data System and the Scientific Registry of Transplant Recipients databases later provided a valuable measure of the impact of MMF in improving outcomes. In this review, we provide a synopsis of the prospective studies, including but not limited to the pivotal MMF approval trials, and analyses of the national transplant registries relevant to the long-term impact of MMF in kidney transplantation. Indeed, a substantial body of evidence has shown MMF treatment improves patient survival, graft survival, and death-censored graft survival in kidney transplantation. The beneficial effects of MMF have been particularly notable in high-risk recipients such as African Americans. In coming years, these benefits will require reevaluation in the context of the growing use of novel protocols combining MMF with tacrolimus or sirolimus.

Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL. We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p < 0.001) and death-censored graft survival (p < 0.001) as compared to TAC/MMF (N = 27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI = 1.32, 1.63) and for CsA/SRL 1.38 (95% CI = 1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5–12.6%) and not different between groups. In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.

Preservation techniques are crucial to deceased donor kidney transplantation (DDTx), but the efficacy of pulsatile perfusion (PP) versus cold storage (CS) remains uncertain. We describe patterns of PP use and explore four fundamental questions. What kidneys are selected for PP? How does PP affect utilization of donated kidneys? What effect does PP have on outcomes? When does PP appear to be most efficacious? We examined rates of PP in DDTx in the United States from 1994 to 2003. We generated models for organ utilization, delayed graft function (DGF) and for the use of PP. We analyzed the long-term effect of PP with multivariate Cox models. The utilization rates for non-expanded criteria donors (ECDs) were similar by storage type, but for ECDs there was a significantly higher utilization rate with PP (70% with PP vs. 59% with CS, p < 0.001). Use of PP was widely variable across transplant centers. DGF rates were significantly lower with PP (27.6% vs. 19.6%). PP was associated with a mild benefit on death censored graft survival (adjusted hazard ratio = 0.88, 95% CI 0.85-0.91). Reduced DGF and significantly lower discard rates of ECDs associated with PP suggest an important utility of PP in renal transplantation. Additional evidence of improvement in graft survival, particularly in more recent years, provides further encouraging evidence for the use of PP.

Background Dendritic cells (DCs) are potent antigen-presenting cells that induce and regulate immune responses. Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid DC populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. Methods Using flow cytometry, PBDC levels were quantified in patients with end-stage renal disease (ESRD) undergoing renal transplantation. Results PBDC levels were significantly reduced in ESRD patients pretransplantation compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving antilymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pretransplant values concurrent with overall reduction of immunosuppression. Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall immunosuppression. Conclusions Our findings suggest that PBDC levels may reflect the degree of immunosuppression in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss, and infectious complications.

To evaluate the association between a regimen of cyclosporine microemulsion (CsA) + sirolimus (Rapa) treatment versus CsA and mycophenolate mofetil (MMF) and renal allograft survival, we analyzed 23 016 primary recipients reported to the Scientific Registry of Transplant Recipients between January 1, 1998 and July 26, 2003. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models correcting for demographic and clinical covariates were used to estimate the relative risks for CsA+Rapa versus CsA+MMF-treated patients reaching study endpoints. Subgroup analyses were conducted for recipient ethnicity and donor type. CsA+Rapa was associated with significantly lower graft survival (74.6% vs. 79.3% at 4 years, p = 0.002) and death-censored graft survival (83.7% vs. 87.2%, p = 0.003) compared to CsA+MMF. In multivariate analyses, CsA+Rapa was associated with a significantly increased risk for graft loss, death-censored graft loss and decline in renal function (HR = 1.22, p = 0.002; HR = 1.22, p = 0.018 and HR = 1.25, p < 0.001, respectively). Similar results were obtained in recipient ethnicity and donor type subgroups. In summary, CsA+Rapa was associated with significantly worse graft survival and death-censored graft survival compared to CsA+MMF, and likely reflects full-dose CsA +Rapa. Outcomes regarding alternative strategies of Rapa utilization with reduced CsA, with alternative agents or with no calcineurin inhibitor cannot be extrapolated from these data.

Dendritic cells (DCs) are key antigen-presenting cells with a potential role in tumor vaccines. We investigated the hypothesis that early reconstitution of DCs after allogeneic hematopoietic stem cell transplantation (SCT) improves survival. We also correlated DC reconstitution with complications of relapse and acute graft-versus-host disease (aGVHD). Fifty patients underwent transplantation between February 2000 and March 2003, with a median follow-up of 501 days (range, 136-1263 days). Most (92%) received blood stem cells, and the remainder received bone marrow from HLA-matched sibling donors for predominantly high-risk hematologic malignancies. Around the time of engraftment, peripheral blood underwent flow cytometry analysis for DCs, and the cells were divided as DC1 and DC2. Using Kaplan-Meier analysis, patients with lower DC counts (< 4.97 cells/μL) were found to have significantly worse survival (P = .002), increased incidence of relapse (P = .002), higher incidence of aGVHD onset (P = .0005), and a composite end point of relapse or death (P = .0017). A Cox proportional hazards multivariate model adjusted for important covariates confirmed that low DC count is independently associated with death (hazard ratio [HR], 3.8; P = .02), time to relapse (HR, 11.6; P = .001), and aGVHD (HR, 3.3; P = .04). Sensitivity and specificity rates for low DC count in predicting death or relapse are 73% and 75%, respectively. Low numbers of circulating DCs significantly increase the risk for relapse and acute GVHD and predict death after allogeneic SCT. (Blood. 2004;103:4330-4335)

Acute rejection is known to have a strong impact on graft survival. Many studies suggest that very low acute rejection rates can be achieved with current immunosuppressive protocols. We wanted to investigate how acute rejection rates have evolved on a national level in the U.S. and how this has impacted graft survival in the most recent era of kidney transplantation. For this purpose, we analyzed data provided by the Scientific Registry of Transplant Recipients regarding all adult first renal transplants between 1995 and 2000. We noted a significant decrease in overall acute rejection rates during the first 6 months, during the first year, and also in late rejections during the second year after transplantation. Despite this decrease in the rate of acute rejection, there was no significant improvement in overall graft survival; furthermore, we noted a statistically significant trend towards worse death-censored graft survival. There was also a trend for a greater proportion of rejection episodes to fail to recover to previous baseline function after treatment. Our data suggest that decreasing acute rejection rates between 1995 and 2000 have not led to an increase in long-term graft survival. Part of this discordance might be related to a higher proportion of acute rejections which have not resolved with full functional recovery in more recent years. However, the etiology of this concerning trend for worse death censored graft survival in recent years will warrant further investigation.

Cyclosporine and tacrolimus share the same pharmacodynamic property of activated T-cell suppression via inhibition of calcineurin. The introduction of these drugs to the immunosuppressive repertoire of transplant management has greatly improved the outcomes in organ transplantation and constitutes arguably one of the major breakthroughs in modern medicine. To this date, calcineurin inhibitors are the mainstay of prevention of allograft rejection. The experience gained from the laboratory and clinical use of cyclosporine and tacrolimus has greatly advanced our knowledge about the nature of many aspects of immune response. However, the clinical practice still struggles with the shortcomings of these drugs: the significant inter- and intraindividual variability of their pharmacokinetics, the unpredictability of their pharmacodynamic effects, as well as complexity of interactions with other agents in transplant recipients. This article briefly reviews the pharmacological aspects of calcineurin antagonists as they relate to the mode of action and pharmacokinetics as well as drug interactions and monitoring.

Both medical care and pharmaceutical development have led to an increase in expected graft and patient survival for patients who undergo renal transplantation. From a research perspective, it has become increasingly difficult to study the efficacy of new therapies using traditional 'hard' endpoints. In reaction to this dilemma, the transplant community has sought a surrogate endpoint. A natural candidate for a surrogate marker for graft loss that has been proposed is renal function (serum creatinine or calculated GFR levels). Using data from the USRDS, we conducted a retrospective evaluation of transplant data from 1988 to 1999 to quantify the predictive value of renal function for the outcomes of graft loss, death-censored graft loss, and patient death. Renal function along with the change in renal function demonstrated a high relative risk for ultimate graft survival and graft loss (odds ratio = 2.2 for an increase of 1 mg/dL). However, the predictive value as measured by the area under the receiver operating characteristic curve (AUC) for this criteria was poor (0.627). These findings held true for the slope of creatinine and formulations of GFR. While renal function is a strong risk factor and highly correlated with graft failure, the utility of renal function as a predictive tool for graft loss is limited.

This review focuses on the use of mycophenolate mofetil (MMF) as an immunosuppressive agent in solid-organ transplantation. MMF, a non-competitive inhibitor of inosine monophosphate dehydrogenase, blocks de novo purine synthesis in T and B lymphocytes, resulting in the selective inhibition of proliferation of these cells in response to antigenic stimuli. MMF may also promote apoptosis of these cells. The immunosuppressive ability of MMF is thought to derive mainly from the inhibition of inosine monophosphate dehydrogenase. The other effects of MMF include suppression of antibody synthesis by B lymphocytes, inhibition of proliferation of smooth muscle cells in culture and impaired glycosylation of adhesion molecules. MMF may exhibit anti-inflammatory effects resulting from decreased activity of the inducible form of nitric oxide synthase, a consequence of depletion of tetrahydrobiopterin, which leads to decreased generation of peroxynitrite, a pro-inflammatory molecule. The pharmacokinetics, pharmacodynamics and principles underlying therapeutic drug monitoring of MMF are reviewed. The results of the pivotal clinical trials of MMF in kidney and heart transplantation are discussed and a summary of the major studies demonstrating a positive effect of MMF on renal transplantation outcomes is presented. The use of MMF in the context of ABO-incompatible renal transplantation, renal transplantation in highly sensitised and cross-match positive recipients, humoral rejection of renal allografts, chronic allograft nephropathy and steroid/calcineurin inhibitor minimisation in renal transplantation are also discussed.