Posttransplant Month Research Articles

Unusual Pattern of Dyslipidemia in Children Receiving Steroid Minimization Immunosuppression after Renal Transplantation

Corticosteroids are an important contributor to posttransplant hyperlipidemia. Since 2004, we have used a steroid minimization immunosuppression protocol. This study investigated the effect of steroid minimization on dyslipidemia in pediatric renal allograft recipients. Children (<18 years) who underwent renal transplants at our center from January 2001 to January 2008 were studied. Data analyzed included age, gender, race, body mass index, cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, and steroid dose. Data between the cohorts receiving maintenance steroids and steroid-minimization were compared using multivariable analyses. The primary outcome measures were the prevalence of, and the effect of steroid use, on dyslipidemia. Twenty-nine patients were studied. Sixteen were receiving maintenance steroids, and 13 were on a steroid minimization regimen. Mixed effects analysis of covariance models demonstrated that at 1 month, children receiving maintenance steroids had higher cholesterol compared with the steroid minimization group. Statistically significant differences in total cholesterol were not seen at other time points. Similar findings were noted for the LDL cholesterol, LDL/HDL, and cholesterol/HDL ratios. At 1 month, the serum HDL cholesterol was substantially lower in the steroid minimization group. Differences in the HDL cholesterol levels remained significant throughout the first year. Steroid use is a significant independent risk factor for hypercholesterolemia during the first post-transplant month. The significance of lower HDL cholesterol among patients receiving steroid minimization needs further study and may be cause for concern.

The Clinical Significance of Early Proteinuria After Renal Transplantation

Late-onset proteinuria after renal transplantation has been universally associated with poor allograft outcomes. However, the significance of early low-grade posttransplant proteinuria remains uncertain. We analyzed the effect of proteinuria 3 months posttransplantation on death-censored graft loss, death with a functioning graft, vascular events within the graft's life, and estimated glomerular filtration rate at 5 years. Four hundred seventy-seven renal transplants from a single center (1988-2003) with a mean follow-up of 122 months were divided into four groups based on the median protein creatinine ratio (PCR) during the 3rd posttransplant month (PCR<0.15 [group 1, n=85]; PCR 0.15-0.5 [group 2, n=245]; PCR 0.5-1.00 [group 3, n=96]; PCR>1.00 [group 4, n=51]). Cox proportional hazards analysis was performed to study the impact of proteinuria on the various outcomes. Multivariate analysis revealed that even low-level proteinuria at 3 months predicted death-censored graft failure (group 1 [reference]--hazard ratio [HR]=1, group 2--HR=7.1, group 3--HR = 10.5, group 4--HR 16.0; P=0.001). The impact on death and the occurrence of vascular events was only significant for group 4 (HR: 2.6; P=0.01 for death and HR: 2.2; P=0.04 for vascular events). Estimated glomerular filtration rate at 5 years was group 1, 48.5 mL/min; group 2, 41.2 mL/min; group 3, 31.1 mL/min; and group 4, 24.5 mL/min (P<0.001). Continued observation of group 2 to 1 year revealed adverse outcomes with increasing proteinuria. Low-grade proteinuria at 3 months is associated with adverse clinical outcomes and identifies high-risk group of patients who may benefit from further intervention.

Microbial epidemiology and outcome of bloodstream infections in liver transplant recipients: An analysis of 259 episodes

Bloodstream infections (BSIs) are a major cause of mortality in liver transplant recipients. The incidence, microbiology, and outcome of BSIs in the first year after liver transplantation were analyzed in 704 patients who underwent transplantation at a single center between 1997 and 2007. BSIs occurred in 205 (29.1%) of the 704 patients. Overall, 259 episodes were documented, and they resulted in an incidence rate of 36.8%. Of these episodes, 39.4%, 27.8%, 17%, and 15.8% occurred in the very early period (< or = 10 days after liver transplantation), the early period (days 11-30), the intermediate period (days 31-90), and the late period (days 91-365), respectively. The most frequent pathogens were Enterobacteriaceae members (41%), Staphylococcus aureus (19.8%), enterococci (13.1%), Pseudomonas aeruginosa (8.8%), and yeasts (7.1%). The median time of onset ranged from 7 days for methicillin-resistant S. aureus to 25 days for Enterobacteriaceae. Mortality at 15 days after BSIs was 16.2%. Kaplan-Meier survival curves showed that patients with BSIs had a significantly higher 1-year mortality rate than those without BSIs (28.3% versus 16.6%, P < 0.001 with the log-rank test). When the time of BSI onset was considered, 1-year mortality was significantly associated with very early and early episodes (P < 0.001) but not with intermediate and late episodes (P = 0.47). In conclusion, BSIs are frequent and early complications after liver transplantation and are mostly caused by gram-negative bacilli. A BSI in the first posttransplant month is a significant predictor of 1-year survival.

Risiken nach Nierentransplantationen – Maximale Nachbetreuung minimiert Infektionswahrscheinlichkeit

Infektiöse Komplikationen nach einer Nierentransplantation sind häufig. Verursacht werden sie hauptsächlich durch Bakterien und Viren. Die Inzidenz wird in der Literatur mit 20–60 % angegeben. Bedingt werden sie in 1. Linie durch die erforderliche Immunsuppression nach einer Transplantation. Allerdings spielen auch das Alter des Patienten, die Dauer der Dialysezeit sowie andere Faktoren, wie etwa ein Diabetes mellitus und der Lebensstil, eine große Rolle. Hohe Aufmerksamkeit sollten die frühzeitige Erkennung und Behandlung solcher Komplikationen bekommen. Selbstverständlich kann eine zielgerichtete Prophylaxe zur „Eindämmung” einer Infektion beitragen. Deshalb ist es wichtig, dass ein erfahrenes Transplantationsteam die Patienten nach der Transplantation überwacht.

Successful High-Dose Ribavirin Treatment of Respiratory Syncytial Virus-Induced Tracheobronchitis and Pneumonia Occuring Pre-Engraftment in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Abstract 1163Poster Board I-185 IntroductionRespiratory syncytial viruses (RSV) frequently cause severe respiratory disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Within the first post-transplant month, progression of upper respiratory tract infection to life-threatening bronchiolitis and pneumonia is common and mortality rates of up to 80% have been reported if left untreated. Aerosolized ribavirin plus/minus immunoglobulins is considered the treatment of choice for RSV pneumonia. With this regimen, the 30-day all cause mortality is still 40% in immunosuppressed HSCT patients. In addition, nebulizing ribavirin may induce toxic side effects on patients and staff. Patients and treatmentConcurrent with an outbreak in the community, RSV infection was diagnosed in 10 out of 29 patients (34%) undergoing allogeneic HSCT in the winter season 2008. Diagnosis was based on RSV-specific PCR of routinely collected throat swaps. Intravenous ribavirin was dosed according to Schleuning et al., 2003 (day 1: 33 mg/kg, day 2-5: 4×16 mg/kg, day 6-10: 3×8 mg/kg) for 8-10 days, followed by oral ribavirin (1800 mg per day) until recovery from symptoms. Airflow obstruction (AFO) was defined as a FEV1/FVC ratio <0.7 or a drop in FEV1 >20% from baseline. All RSV-infected patients (median age 60 years) had undergone reduced-intensity conditioning HSCT for high-risk acute myeloid leukemia (1st CR: n=2; subsequent CR: n=3; untreated or refractory relapse: n=5). GvHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil with (n=8) or without (n=2) antithymocyte globulin. Donors were HLA-idential siblings (n=1), matched (n=8) or mismatched unrelated donors (n=1). ResultsMedian time from HSCT to detection of RSV was 15 (range, 1-40) days. In 7 out of 10 patients, RSV infection was diagnosed pre-engraftment during neutropenia. Four patients had bronchiolitis or pneumonia and 6 patients suffered from tracheobronchitis. High-dose intravenous ribavirin was administered to all patients with pneumonia and/or diagnosis of RSV infection within 7 days after transplantation (n=5). These patients had hypoxia and required oxygen supplementation. Treatment with oral ribavirin was initiated in the other five patients with tracheobronchitis diagnosed on days 12-40 after HSCT. With a median follow up of 6 months, 9 out of 10 patients are alive and in complete remission of their AML. All 9 patients became RSV-negative in throat swabs after a median time of 22 days from start of therapy. Severe AFO caused by RSV pneumonia occurred in 2 patients and improved after treatment. Despite severe lymphopenia, no patient treated for tracheobronchitis progressed to RSV pneumonia. Neutrophil recovery was delayed in the three patients diagnosed with RSV pneumonia pre-engraftment until days 26, 28+ and 111 after HSCT, due to high-dose intravenous ribavirin and/or RSV infection itself. One of these patients died of septic shock associated with pseudomonas aeruginosa-induced pneumonia on day 28 after HSCT in prolonged neutropenia. No other ribavirin-associated toxicity such as hepatotoxicity or clinically relevant hemolysis was observed. Three patients developed acute intestinal GvHD, 2 of them recovering upon steroid treatment and one proceeding to chronic disease despite salvage therapy. One additional patient had steroid-responsive acute GvHD of the skin. ConclusionsHigh-dose intravenous or oral ribavirin therapy appears to be safe and effective even if administered to neutropenic allogeneic HSCT recipients. None of these patients with RSV infection in the early post-transplant period developed bronchiolitis obliterans or persistent AFO. Based on our favourable results, further studies are required. Meanwhile, we suggest to treat all patients with symptomatic RSV infections in the early post-transplant phase with oral or intravenous ribavirin. DisclosuresOff Label Use: Ribavirin is approved for inhalative treatment of RSV infections but not for systemic therapy..

Adequate Immune Reconstitution in Recipients of Unrelated Donor Hematopoietic Cell Transplants Given Rabbit Anti-Thymocyte Globulin During Conditioning.

Abstract 2234Poster Board II-211Anti-thymocyte globulin (ATG) is known to reduce the risk of developing acute graft vs host disease following allogeneic hematopoietic cell transplant (HCT). Its effects on long-term immune reconstitution are less well defined, particularly in the adult population undergoing unrelated donor (URD) HCT. Since 2004, rabbit ATG (Thymoglobulin, Genzyme Inc, Cambridge, MA) has been used at our institution during the conditioning of patients undergoing URD HCT. We performed a retrospective landmark analysis to compare immune reconstitution in patients who received ATG during conditioning vs. those who did not. Patients had to have completed at least 6 months of follow-up post transplant. Eighty six patients were eligible, and underwent analysis of immune reconstitution in the first year post transplant. Fifty six patients underwent matched related donor HCT and did not receive ATG (no ATG cohort); 30 patients received an URD HCT (ATG cohort). The median age for no ATG cohort was 49 years and for the ATG cohort was 48. There were 40 females in the combined cohorts. The no ATG cohort included patients with the diagnosis of AML (34%), NHL (21%), MM (16%), ALL (9%), along with CML, CLL, MDS, MF and HD (20%). The ATG cohort was comprised of AML (43%), MDS (23%), ALL (13%), CML (13%), along with NHL & SAA (8%). Conditioning regimens used in the no ATG vs. ATG cohorts were 12-Gy TBI-Cy in 18% vs. 47%, Bu-Cy in 42% vs. 40%, and others in 40% vs. 13% (Flu-Mel, Bu-Flu, Flu-Cy, 2-Gy TBI,TBI-VP16). Stem cells were GCSF mobilized PBSC in 95% of the no ATG cohort and in 44% of the ATG cohort. The ATG dose administered was either 7.5 or 10 mg/kg in 3 divided doses, given from day -3 to day -1. With a median follow up of 727 days in the no ATG cohort and 480 days in the ATG cohort, 82% of the patients survived in the no ATG cohort compared to 73% in the ATG cohort (Fisher's exact test P=0.41). Absolute lymphocyte counts at 6, 9 and 12 months following transplantation were (mean ± SD) 1.2 ± 0.6×10 3 /μL vs. 1.0 ± 0.8 (T-Test, P=0.44), 1.5 ± 0.9 vs. 1.3 ± 1.0 (P=0.51) and 1.6 ± 0.9 vs. 1.3 ± 0.9 (P=0.23) respectively in the no ATG cohort vs. ATG cohort. Lymphocyte subset enumeration data was obtained during the first year following HCT at the time of cessation of immunosuppression and was available for 32 and 12 patients in the no ATG and ATG cohorts respectively. Absolute CD3+ cell counts measured at a median of 278 days were 1226 ± 773 vs. 981 ± 442 /μL in the no ATG vs. ATG cohorts (P=0.52). Simultaneously measured absolute CD3+/4+ cell counts were 483 ± 231 vs. 242 ± 122 (P=0.001), CD3+/8+ were 717 ± 627 vs. 701 ± 444 (P=0.94), CD19+ were 250 ± 239 vs. 351 ± 233 (P=0.25) and CD56+ were 181 ± 97 vs. 178 ± 67 (P=0.75) in the no ATG vs. ATG cohorts. Surveillance for EBV and CMV reactivation was performed using PCR. No statistically significant difference was noted in rate of CMV reactivation between the two cohorts in the 6-12 month post-transplant period indicating equivalent functional cellular immune reconstitution. EBV reactivation did not occur in either cohort. During the same time period the incidence of culture proven fungal infections and viral infections was equivalent between the two groups, however there was a significantly higher number of patients who experienced bacterial infection episodes in the ATG group. We are investigating the impact of ATG administration on the relative rate of relapse in these two cohorts. We conclude that ATG administered during conditioning did not adversely impact cellular immune reconstitution in this cohort of patients, even though these high-risk patients had undergone URD HCT with bone marrow as the stem cell source in the majority. This effect may be explained by a reduction in the incidence of acute GVHD secondary to ATG use, which in turn reduces the overall immunosuppressive exposure these patients experience following transplantation. T helper cell reconstitution appears to be delayed and may contribute to the higher number of patients experiencing bacterial infections in the ATG cohort. Disclosures:Off Label Use: Thymoglobulin for GVHD prophylaxis. McCarty:Celgene: Honoraria; Genzyme: Honoraria.

The Evolution of Kidney Function After Lung Transplantation: A Retrospective Cohort Study

Background Little information exists regarding the rate of kidney functional loss after lung transplantation. The aim of this study was to assess the evolution of kidney function after lung transplantation, seeking to identify a pretransplant glomerular filtration rate (GFR) threshold under which dual lung-kidney transplantation should be considered. Patients and methods We performed a single-center, retrospective cohort study among patients who received a first lung transplant. GFR was measured with the MDRD7 equation immediately before and up to 10 years after transplantation. A hierarchical model of linear regression was used to determine the evolution of GFR over time. Results We studied 241 subjects whose mean GFR was 92 ± 33 mL/min/1.73 m 2 immediately before transplantation. The GFR declined quickly during the first posttransplant month (−24 mL/min/1.73 m 2 vs baseline; 95% confidence interval [CI]: −27, −21 mL/min/1.73 m 2). It decreased slightly between 1 and 12 months (−34 mL/min/1.73 m 2 at 12 months vs baseline; 95% CI: −37, −31 mL/min/1.73 m 2) and then stabilized up to 10 years after transplantation. GFR loss varied according to the baseline GFR. In patients with baseline GFR ≤ 60 mL/min/1.73 m 2, the GFR declined by 9 mL/min/1.73 m 2 (95% CI = 6–15) at 1 year and was stable there after. Conclusion GFR declines rapidly in the first month and at 1 year after lung transplantation, stabilizing thereafter. Because they are likely to develop eligibility for kidney transplantation in the 1 to 2 years following lung transplantation, we believe that dual lung-kidney transplantation should definitely be considered for subjects with a baseline GFR ≤ 35 mL/min/1.73 m 2.

Indoleamine 2,3-Dioxygenase in Lung Allograft Tolerance

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the degradation of tryptophan (Try) to kynurenine (Kyn), is thought to suppress T-cell activity. Although a few experimental studies have suggested a role for IDO in graft acceptance, human data are scarce and inconclusive. We sought to establish whether, in lung transplant recipients (LTRs), plasma IDO activity mirrors the level of graft acceptance. We measured the plasma Kyn/Try ratio, reflecting IDO activity, by high-performance liquid chromatography (HPLC) in 90 LTRs, including 26 patients who were still functionally/clinically stable for >36 post-transplant months (stable LTRs) and 64 LTRs with bronchiolitis obliterans syndrome (BOS, Grades 0-p to 3). Twenty-four normal healthy controls (NHCs) were also included. The Kyn/Try ratio in stable LTRs resembled that observed in NHCs, whereas, unexpectedly, patients with BOS, who had lower counts of peripheral CD4(+) T-regulatory cells and tolerogenic plasmacytoid dendritic cells than stable LTRs, showed an increased plasma Kyn/Try ratio compared with both NHCs and stable LTRs. IDO expression by in vitro-stimulated peripheral blood mononuclear cells (PBMC) did not vary between BOS and stable LTRs. Furthermore, BOS patients displayed signs of chronic systemic inflammation (increased plasma levels of interleukin-8 and tumor necrosis factor-alpha) and higher T-cell activation (increased frequency of peripheral interferon-gamma-producing clones). Our results suggest that, in vivo, in lung transplantation, plasma IDO activity does not reflect the degree of lung graft acceptance, but instead is correlated with the degree of chronic inflammation.

Sustained BK Viruria as an Early Marker for the Development of BKV-Associated Nephropathy: Analysis of 4128 Urine and Serum Samples

BKV reactivation plays the causative role in the development of BKV-associated nephropathy (BKVAN). Because of the lack of effective therapy, early diagnosis of BKV reactivation is paramount for the prevention of BKVAN. Resting in uroepithelial cells, BKV is excreted first in urine before it can be detected in plasma. The present study analyzed predictive value of BK viruria for the development of BK viremia and its possible advantage for the early BKVAN prediction. Total of 4128 urine and serum samples obtained from renal transplant patients were analyzed for BKV positivity by real-time polymerase chain reaction in 433 patients in cross-sectional and in 233 patients in longitudinal manner, respectively. The prospective longitudinal analysis included seven measurements during the first posttransplant year. A total of 7% and 19% patients were positive for BKV in serum and urine, respectively. Sustained BK viruria showed sensitivity of 100% and specificity of 94% for BK viremia and was associated with significantly higher level of BK load than the patients with transient viruria (P<0.01). Interestingly, BK viremia was preceded by BK viruria: the peak of viral load and number of positive patients appeared during the third and fifth posttransplant month for urine and serum, respectively. BKVAN diagnosed in 21.4% of patient with persistent BK viruria appeared 5 and 11 weeks after BKV reactivation in serum and urine, respectively, was detected. Sustained BK viruria is a reliable marker allowing an early identification of patients at high risk of BKVAN development and therefore assure precocious therapeutic interventions.

Differences in Baseline Lymphocyte Counts and Autoreactivity Are Associated With Differences in Outcome of Islet Cell Transplantation in Type 1 Diabetic Patients

OBJECTIVEThe metabolic outcome of islet cell transplants in type 1 diabetic patients is variable. This retrospective analysis examines whether differences in recipient characteristics at the time of transplantation are correlated with inadequate graft function.RESEARCH DESIGN AND METHODSThirty nonuremic C-peptide–negative type 1 diabetic patients had received an intraportal islet cell graft of comparable size under an ATG-tacrolimus–mycophenolate mofetil regimen. Baseline patient characteristics were compared with outcome parameters during the first 6 posttransplant months (i.e., plasma C-peptide, glycemic variability, and gain of insulin independence). Correlations in univariate analysis were further examined in a multivariate model.RESULTSPatients that did not become insulin independent exhibited significantly higher counts of B-cells as well as a T-cell autoreactivity against insulinoma-associated protein 2 (IA2) and/or GAD. In one of them, a liver biopsy during posttransplant year 2 showed B-cell accumulations near insulin-positive β-cell aggregates. Higher baseline total lymphocytes and T-cell autoreactivity were also correlated with lower plasma C-peptide levels and higher glycemic variability.CONCLUSIONSHigher total and B-cell counts and presence of T-cell autoreactivity at baseline are independently associated with lower graft function in type 1 diabetic patients receiving intraportal islet cells under ATG-tacrolimus–mycophenolate mofetil therapy. Prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first year posttransplantation.

Individual Differences in Cyclosporine A Pharmacokinetics and Its Association with Acute Renal Function Following Heart Transplantation

Background: The secondary metabolites of cyclosporine A (CsA), AM19, AM1c and AM1c9, have been indi- cated to be nephrotoxic. The aim of the present pilot study was to investigate the relationship between acute renal failure and CsA metabolite levels, including relevant pharmacokinetic genotypes, following heart transplantation. Methods: Whole-blood samples were drawn the first posttransplant week in 22 patients (median 54 years, range from 27 to 65). Whole blood concentrations of CsA and its six main metabolites were analyzed with a validated HPLC-MS/MS method, and relevant CYP3A5 and ABCB1 genotypes determined. Renal function was monitored daily during the first posttransplant month and also at months 3, 6 and 12. Results: One patient died early posttransplant. Six patients were in need of dialysis directly after transplantation. Nine pa- tients developed sustained impaired renal function, while six had stable renal function. Sustained renal impairment tended to be associated with high levels of toxic metabolites (P=0.08). Six of the patients with possible ABCB1 TTT-haplotype developed renal impairment (P=0.12). Conclusion: The present study indicates that toxic CsA metabolites seems to be associated with development of impaired renal function and together with ABCB1 genotyping they might be promising biomarkers for optimalization of immuno- suppressive drug treatment in future studies.

Passenger Lymphocyte Syndrome With or Without Immune Hemolytic Anemia in all Rh-Positive Recipients of Lungs From Rhesus Alloimmunized Donors: Three New Cases and a Review of the Literature

The passenger lymphocyte syndrome (PLS) is an unusual complication of solid organ transplantation, in which donor lymphocytes produce antibodies reactive with host red blood cell (RBC) antigens. Risks for PLS include highly lymphoid grafts, past sensitization of the donor against relevant RBC antigens, and donor lymphocyte escape of host immune clearance. For a 1-year period at our center, we observed an uncommonly high frequency of post-lung transplant Rhesus PLS, occurring once in every 31 cases. Passenger lymphocyte syndrome resulted from 2 alloimmunized cadaveric donors, in 3 of 3 D+, ABO-identical but HLA-unmatched recipients who initially had nonreactive RBC antibody screens. In case 1, the right lung of a group A, D-negative donor, with antibodies against D, C, and E antigens, was transplanted into a group A, R1R1 recipient. The recipient developed severe hemolytic anemia, direct antiglobulin test (DAT)-positive, on postoperative day (POD) 17. Anti-D and anti-C were identified on both the indirect antiglobulin test (IAT) and the RBC eluate. She required 10 U of RBCs in 40 days as well as plasmapheresis (POD 36-40). When transfusion dependence ceased, anti-D +/- C remained detectable on DAT and IAT for another 6.5 months. In case 2, the group A, R1r recipient of the same donor's left lung exhibited anti-D for the first time at posttransplant month 4 on both IAT and DAT. This activity persisted until a rejection episode 5 months later, without ever causing any evidence of hemolysis. In case 3, the group O, R1R1 recipient of both lungs of a group O, D-negative donor, with antibodies against D, C, and V antigens, developed a nonhemolytic DAT and IAT with anti-D +/- C at postoperative month 2, which remained positive at last follow-up (6 months posttransplant). In conclusion, this report suggests a high incidence of Rhesus antibody PLS after lung transplantation, with wide variations in the timing of antibody onset, persistence, and severity. A review of the phenomenon and its implications are discussed.

Prospective monitoring of BK virus replication in renal transplant recipients

BK virus-associated nephropathy (BKVAN) can be diagnosed only with renal graft biopsy. Definitive diagnosis of BKVAN requires demonstration of BK virus (BKV) replication in renal allograft tissues. Non-invasive analysis of urine and blood is considered essential in screening renal transplant recipients. This study evaluated prospectively the replication of BKV in plasma and urine with qualitative and quantitative real-time polymerase chain reaction in 32 de novo (group A) and 34 chronic (group B) renal transplant recipients and the long-term impact on graft function. In group A, 456 samples (228 plasma, 228 urine) were examined and BKV was detected in 31 (31/228, 14%) samples of plasma and 57 (57/228, 25%) samples of urine in 20 (20/32, 62.5%) and 23 (23/32, 72%) recipients, respectively. Incidence of viremia and viruria increased during the first 6 months presenting a peak the third postoperative month (viremia: 28% and viruria: 31%). Immune suppressive treatment with tacrolimus showed significant relation with viremia. Renal graft function in de novo renal transplant recipients remained stable throughout the follow-up period without influence of BKV replication. In group B, incidence of viremia and viruria were 3% (1/34) and 9% (3/34) correspondingly, indicating that after the first post-transplant year the risk of BKV re-activation is diminished. The highest incidence of BK viremia and viruria is observed the third post-transplantation month, confirming previously published studies in Europe and the United States, and long-term follow up shows that BKV replication decreases significantly after the third post-transplant month and even transient viremia or viruria does not have an impact on renal function.

Infectious complications in living‐donor liver transplant recipients: a 9‐year single‐center experience

Infectious complications following living-donor liver transplantation (LDLT) remain a major cause of morbidity and mortality. We analyzed the frequency and type of infectious complications according to the post-transplantation period, and their risk factors with regard to morbidity and mortality. We retrospectively analyzed 208 subjects who had undergone LDLT during a 9-year period. The rate of infection was 1.69 per patient during the study period. The predominant infections were intra-abdominal infections (37.6%), primary bacteremia (17.4%), and pneumonia (14.5%). Within the first post-transplant month, 140 (39.9%) infections were detected, and catheter-related coagulase-negative staphylococci (44) were the most common infectious agents. During the 2-6-month post-transplant period, 109 infectious episodes occurred (31.1%), and Enterococcus sp. (n=16) related to biliary infection was the most frequent isolate. After the sixth month, 96 infectious episodes (29%) occurred, and biliary tract-related Escherichia coli (n=19) was the major causative organism. The overall mortality was 24.5% (51/208); 1-year survival rate was 88% (196/208). Post-transplant infection-related mortality was 52.9% (27/51). Biliary tract complications, such as biliary stenosis or leakage, significantly increased the mortality (P=0.01); however, reoperation (retransplantation or resurgery for biliary tract obstruction/leakage or to control bleeding) significantly reduced the mortality (P=0.01). Our data showed that early catheter removal would mainly aid in reducing infectious complications in the 1-month post-transplantation period. Aggressive management, including reoperation, would lower the mortality in the LDLT recipients.

Changes in Cardiac Parameters of Renal Allograft Recipients: A Compilation of Clinical, Laboratory, and Echocardiographic Observations

Introduction This study was undertaken to observe changes in cardiac parameters along with clinical and laboratory changes after renal transplantation. Patients and Methods Cardiac parameters were evaluated by M-mode 2-dimensional echocardiography before transplantation and at monthly intervals. All subjects had functioning grafts at the time of the evaluations. Results Fifty-two allograft recipients underwent pretransplant parameters for comparison to those at posttransplant months 1, 3, 6, and 12. When changes at month 1 and 3 were observed among 22 patients, improvements were evident at month 3. Comparisons of pretransplant versus month 3 showed systolic blood pressure (SBP), 161 ± 16 to 133 ± 26 mmHg ( P < .002); diastolic BP (DBP), 101 ± 9 to 86 ± 11 mmHg, ( P < .006); hemoglobin (Hgb), 7.3 ± 1.6 to 11.2 ± 3.9 g/dL ( P < .006); left atrial diameter (LAD), 41 ± 5 to 35 ± 3 mm ( P < .001); left ventricular muscle mass index (LVMI), 379 ± 114 to 248 ± 58 g/m 2 ( P < .001); and left ventricular end diastolic volume index (LVEDVI), 96 ± 28 to 64 ± 17 mL/m 2 ( P < .002). When changes at months 3, 6, and 12 were observed among 30 patients, improvements evident at month 3 were maintained. Comparisons of pretransplant and 3 and 12 months observations showed SBP, 157 ± 17, 131 ± 14, to 126 ± 10 mm Hg ( P < .001); DBP, 97 ± 10, 83 ± 16, to 85 ± 6 mmHg ( P < .001); Hgb, 7 ± 1, 13 ± 2, to 13 ± 2 g/dL ( P < .001); LAD, 39 ± 7, 35 ± 3, to 34 ± 4 mm ( P < .05); LVMI, 275 ± 91, 191 ± 38, to 159 ± 26 g/m 2 ( P < .001); and LVEDVI, 87 ± 29, 56 ± 34, to 49 ± 24 mL/m 2 ( P < .001). Conclusion Significant improvements in cardiac parameters were evident by the third month post-renal transplantation; the changes were maintained over a longer period among patients with functional grafts.

Association of device surface and biomaterials with immunologic sensitization after mechanical support

Biomaterials and textured surfaces in early pulsatile left ventricular assist devices (HeartMate I; Thoratec Corporation, Pleasanton, Calif) may increase immunologic risk through allosensitization. We hypothesized that axial-flow devices without biologic membranes or textured surfaces (HeartMate II; Thoratec; and DeBakey; MicroMed Cardiovascular, Inc, Houston, Tex) would cause less allosensitization than devices with such membranes and surfaces. HeartMate II and DeBakey (n = 24) and HeartMate I (n = 36) devices were implanted from 1999 to 2006 in patients with severe heart failure cohort-matched for age, etiology, and support duration. Serum samples reacting with more than 10% of the HLA reference panel were considered positive for anti-HLA antibodies. Endomyocardial biopsy samples were collected after transplant. There were no significant cohort differences in age, etiology, sex, blood transfusion, or support duration. Anti-HLA antibodies were not detected at implantation of either HeartMate II and DeBakey or HeartMate I devices; however, significant increases in anti-HLA antibodies were present within 1 and 3 months of support with HeartMate I but not HeartMate II and DeBakey devices. Overall, fewer patients with HeartMate II and DeBakey devices demonstrated positive anti-HLA antibodies during support (8% vs 28%, P = .02), and fewer episodes of acute rejection per patient were seen within the first 9 posttransplant months(0.31 vs 0.69, P = .052). Long-term posttransplant survival was not different between groups. Hemodynamic support with HeartMate II and DeBakey devices produced less allosensitization than did HeartMate I devices. Device selection may improve clinical outcomes for high-risk patients.

Spectrum and risk factors for invasive candidiasis and non-Candida fungal infections after liver transplantation

Invasive fungal infections are an important cause of posttransplant mortality in solid-organ recipients. The current trend is that the incidence of invasive candidiasis decreases significantly and invasive aspergillosis occurs later in the liver posttransplant recipients. The understanding of epidemiology and its evolving trends in the particular locality is beneficial to prophylactic and empiric treatment for transplant recipients. A retrospective analysis was made of recorded data on the epidemiology, risk factors, and mortality of invasive fungal infections in 352 liver transplant recipients. Forty-two (11.9%) patients suffered from invasive fungal infection. Candida species infections (53.3%) were the most common, followed by Aspergillus species (40.0%). There were 21 patients with a superficial fungal infection. The median time to onset of first invasive fungal infection was 13 days, first invasive Candida infection 9 days, and first invasive Aspergillus infection 21 days. Fifteen deaths were related to invasive fungal infection, 10 to Aspergillus infection, and 5 to Candida infection. Invasive Candida species infections were associated with encephalopathy (P = 0.009) and postoperative bacterial infection (P = 0.0003) as demonstrated by multivariate analysis. Three independent risk factors of invasive Aspergillus infection were posttransplant laparotomy (P = 0.004), renal dysfunction (P = 0.005) and hemodialysis (P = 0.001). The leading etiologic species of invasive fungal infections are Candida and Aspergillus, which frequently occur in the first posttransplant month. Encephalopathy and postoperative bacterial infection predispose to invasive Candida infection. Posttransplant laparotomy and poor perioperative clinical status contribute to invasive Aspergillus infection. More studies are needed to determine the effect of prophylactic antifungal therapy in high risk patients.

Comparison of Sirolimus Alone With Sirolimus Plus Tacrolimus in Type 1 Diabetic Recipients of Cultured Islet Cell Grafts

One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy. Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects. At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped. SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.

Pretransplant Donor-Specific Interferon-γ ELISPOT Assay Predicts Acute Rejection Episodes in Renal Transplant Recipients

Interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISPOT) assay is a powerful tool for measuring the frequency of alloantigen-specific T cells, reflecting cellular immunity. We correlated the pretransplant frequencies of donor-specific and third-party–specific IFN-γ ELISPOT tests, with the posttransplant outcomes of 45 recipients of living donor renal transplantations. The mean frequency of pretransplant donor-specific ELISPOT was significantly greater among patients with acute rejection episodes (ARE) than those without ARE (18.0 [12 to 50] versus 8.8 [5 to 30.4]) spots per 200,000 peripheral blood lymphocytes (PBLs; P = .024). A cutoff level of 12 spots per 200,000 PBLs on the donor-specific ELISPOT identified an ARE-positive patient with a sensitivity of 81.8% and a specificity of 64.7%. The recipients with pretransplant donor-specific ELISPOT + showed higher serum creatinine levels and lower glomerular filtration rate (GFR) at 6 posttransplant months ( P < .05). Although the pretransplant third-party-specific ELISPOT results correlated with the donor-specific ELISPOT results ( r = .783; P < .001), there was no significant difference in the third-party ELISPOT results between the ARE-positive and ARE-negative recipients. In conclusion, an analysis of pretransplant donor-specific IFN-γ ELISPOT may identify the posttransplant risk of developing ARE and displaying decreased GFR at 6 months.

Multi-Center Prospective Trial on Conditioning with Treosulfan, Fludarabine and ATG Before Allogeneic HSCT from Unrelated Donors.

This prospective multi-center trial (MiniMud) concerns 27 patients (13 females, 14 males - 56 years[18–65]) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors. The diagnosis and disease status pre-transplant were AML (n=12; 5 CR1, 7 CR2), ALL (n=1; 1 CR2), MM (n=5; 3 PR2,1 PR3, 1 PR4), NHL (n=4; 1 CR1, 2 PR3, 1 PR4), MPS (n=3; 2 stable disease (SD), 1 Relapse), acute RAEB (n=1; 1 progressive disease (PD) and CLL (n=1; 1 PR2). In total, 14 patients were in CR, 9 in PR, 2 in SD, 2 in PD. The median interval between diagnosis and transplant was 27 months [5;171], 24 patients received PBSC and 3 received bone marrow from unrelated 10/10 antigen HLA-identical (high-resolution level). All patients received Fludarabine 30 mg/m2/dx5d, Treosulfan 12 g/m2/dx3d and ATG 2,5 mg/kg/dx3d. After transplant, we observed 2 graft failures, 7 patients developed an AGVHD ≥ grade II (30%). Only 23 patients were eligibile to be analysed after 3 months of follow-up post transplant, 7 patients developed cGVHD (30%) (5 limited and 2 extensive), 12 patients died (7 from TRM causes and 5 from relapse) and 12 patients are alive in CR with a median follow-up of 14 months. Among the global population we defined a low risk subgroup: 17 patients [12 AML (5 CR1, 7 CR2), 1 ALL (CR2), 3 MM (3 PR2) and 1 NHL (CR1)], 2 patients presented an AGVHD ≥ grade II (13%). With a median follow-up of 18 months, 2 patients had a follow-up of less than 3 months, 3 patients developed a cGVHD (20%), 6 patients died (40%) and 9 patients are alive in CR. At one year, the probability of overall survival (OS) and event-free survival (EFS) were 50.4% [32;79], 40% [23;70] for the total population and 60% [37;96], 51.5% [29;90] for the low risk subgroup respectively. To try to demonstrate if Treosulfan allowed a better transplant outcome we performed a paired match-analysis [center and 4 out of 5 other parameters (age, gender, HSC, pre-transplant status and diagnosis] comparing our Treosulfan series and RIC transplants receiving Fludarabine, Busulfan and ATG (2.5–12.5mg/kg) from the SFGM-TC registry. This paired match-analysis found only RICT from related donors in the SFGM-TC database and showed no difference in term of OS and EFS between our unrelated donor-Treosulfan and related donor-SFGM-TC series. [Display omitted] [Display omitted] In conclusion, these results demonstrate that Treosulfan appears to be a very promising drug that could be included in the conditioning regimen before HSCT from either related or unrelated donors.