Higher Incidence Of Graft Failure Research Articles

Influence of Glutathione S-Transferase A1 and P1 Polymorphisms on the Outcome of Hematopoietic Stem Cell Transplantation with Busulfan Based Conditioning Regimen In Children.

AbstractAbstract 3492 Introduction:Busulfan has narrow therapeutic range. High exposure is associated with systemic toxicity such as veno-occlusive disease (VOD) while underexposure results in graft failure or relapse. In children, pharmacokinetic variability was found to be high even after the introduction of intravenous busulfan. Busulfan is metabolized via liver through conjugation with glutathione S-transferase (GST) family, and inter-individual variability may be explained by GST polymorphisms. Thus, we investigated the influence of GST polymorphisms on the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with busulfan based conditioning regimen in children. Patients and methods:We studied patients who underwent HSCT at Seoul National University Children's Hospital from November, 2001 to November, 2008. IV busulfan (0.8 mg/kg/dose for patients≥10 kg and 1.1 mg/kg/dose for patients <10 kg, q 6hr for 4 days) was used in combination with cyclophosphamide or fludarabine as conditioning regimen. Etoposide was added for acute lymphocytic leukemia (ALL). GST polymorphisms (GSTA1 375 A > G, -52 G > A, -567 G > T, -631 G > T, -69 C > T, GSTM1 deletion, GSTT1 deletion, and GSTP1 313 A > G) were analyzed by multiplex PCR amplification and SNP genotyping. Results:A total of 70 patients (48 male, 22 female) were analyzed. The diagnoses were ALL in 32, AML in 26, and other diseases in 12 patients. Median age at HSCT was 8.8 years (range 1.0–19.0 years). Bone marrow or peripheral blood stem cell transplantations (BMT/PBSCT) were conducted in 42 patients, and cord blood transplantations (CBT) in 28 patients. Graft failure occurred in 11 (15.7%) patients (1 (2.4%) in BMT/PBSCT, 10 (35.7%) in CBT) and relapse occurred in 15 (21.4%) patients (12 (28.6%) in BMT/PBSCT, 3 (10.7%) in CBT) after HSCT. Patients having GSTA1 *A/*A and GSTP1 313 A/A genotype (N=33) showed higher incidence of graft failure than the others (N=37) (27.3% vs 5.4%, P =.01). Conversely, the incidence of hyperbilirubinemia over grade 3 was significantly lower in the patients with GSTA1 *A/*A and GSTP1 313 A/A genotype than the other patients (6.1% vs 24.3%, P =.05). Event free survival (EFS) of patients with GSTA1 *A/*A and GSTP1 313 A/A genotype was significantly lower than the EFS of the other patients in both BMT/PBSCT and CBT, and the main causes of event were graft failure in CBT and relapse in BMT/PBSCT. Conclusions:In children undergoing HSCT with busulfan based conditioning regimen, GST A1 and P1 polymorphisms seem to have influence on the graft failure, relapse and complications. To confirm our results, further studies about the influence of GST A1 and P1 polymorphisms on the pharmacokinetics of busulfan are needed. Disclosures:No relevant conflicts of interest to declare.

The role of reduced intensity preparative regimens in patients with thalassemia given hematopoietic transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) still remains the only curative treatment for patients with thalassemia major (TM). However, HSCT is associated with a non-negligible risk of both transplantation-related mortality (TRM) and morbidity. Great interest and relevant expectations have been raised by the introduction in the clinical practice of reduced-intensity preparative regimens, which may represent an effective strategy to reduce the toxicity of transplantation and may also help reduce the incidence of late effects. Although some reports have documented the feasibility of using reduced-intensity preparative regimens for successfully treating patients with TM, a high incidence of graft failure has been frequently reported. Recently, treosulfan-based myeloablation has been demonstrated to be associated with limited extra-medullary toxicity and a high rate of sustained donor engraftment. This novel approach is a promising alternative for reducing the risk of life-threatening complications and increasing the number of TM patients successfully cured with an allograft.

Prevalence and Significance of Pre-Formed Anti-HLA Antibodies in Hematopoietic Stem Cell Transplant Recipients.

Abstract 1174Poster Board I-196 Introduction:The presence of sensitization to HLA antigens has been an important consideration in solid organ transplantation. It is considered a standard process to check for donor-specific allogeneic (allo) antibodies (DSA) and monitor formation of such antibodies post-transplant which could predict early and late graft failure. Most of the current data regarding the importance of anti-HLA (human leukocyte antigen) antibodies is available from renal transplant where presence of HLA antibodies is clearly associated with an increased risk of early graft loss up to the magnitude of 21%. It is routine to perform desensitization to alleviate these antibodies in an effort to enhance their chances of engraftment. The role of and approach to prior sensitization in the hematopoietic stem cell transplantation (HSC) setting is far less clear. This is of unique importance as a wider range of donor cell sources and transplant applications are utilized to treat hematologic diseases. Many of our patients have had multiple transfusions in the past, been pregnant or have had prior HLA mismatched allograft, all of which predispose to development of anti-HLA antibodies. Here we analyze the prevalence of Class I and Class II antibodies as a primary goal and also see if they correlate with graft survival. Methods:52 patients were followed between July 2008 and July 2009 with hematologic malignancies including leukemia's, lymphoma's, multiple myeloma and others. 37/52 underwent transplantation of which 14 were unrelated donor (URD), 5 cord blood (CB) and 8 sibling (sib) transplants. Donors with corresponding HLA were excluded. Post-transplantation with day 100 antibody testing was performed in eligible patients. Antibody determination was done by testing the patients' sera with a panel of fluorescent beads coated with single HLA antigens using a solid-phase Luminex™ platform. Cut-point of 1500 [mean fluorescence intensity (MFI) ≥ 1500 defined as positive] was used for performing statistical analyses. The prevalence of positive antibody levels was compared among the transplant groups using a Fisher's exact test. Level of expression of antibodies was evaluated with MFI <500 considered negative, 500-1500 weak, 1500-3000 intermediate and >3000 strong. High resolution HLA typing was performed. Results:Class I antibodies were positive in 24 out of 52 total (46%) with 95% CI: 32% to 61%.14/37 (38%) who underwent transplantation (95% CI: 22% to 55%), 12/27 (44%) undergoing allo transplant, CB (20%), sib (38%), and URD (57%) were positive. The prevalence did not differ significantly among the transplant groups (p=0.3). Class II antibodies were positive in 8 out of 52 total (15%) with 95% CI: 7% to 28%. 5/37 (14%) who underwent transplantation (95% CI: 5% to 29%), 4/27 (15%) undergoing allo transplant, Sib (0%), CB (20%) and URD (21%) were positive. The prevalence did not differ significantly among the transplant groups (p=0.6). In females, 18/28 (64%) were positive for Class I or Class II antibodies of which 5/6 (83%) underwent URD transplants. Persistent antibody levels were detected in 3 of 4 patients tested at day 100 post transplant. Conclusions:Based on this limited pilot study we conclude that there is a high prevalence of anti-HLA antibodies present in recipients at the time of HSC transplantation. However detection of such antibodies did not jeopardize engraftment from various donor sources when HLA donor specific reactions are excluded. Bray et al showed higher incidence of graft failure associated with DSA. Takanashi et al showed that in CB transplants, antibodies were not significant unless the corresponding HLA was present in the CB unit. Based on these studies, we excluded donors with corresponding HLA. All but one patient, in whom donor specific anti-HLA antibodies were identified, achieved sustained marrow engraftment. The long term implications of antibody evolution and specificity to sustained marrow engraftment, graft vs. host and graft vs. tumor effects remain to be clarified. A larger prospective study will need to be conducted to definitely evaluate these relationships including our own which is currently under way.Class I (MFI)Transplant typen<500500-15001500-3000>3000Pre154146URD142435Sib84112CB52201Auto105320Total5217111014Class II (MFI)Transplant typen<500500-15001500-3000>3000Pre158412URD147421Sib84400CB52201Auto109010Total52301444 Disclosures:No relevant conflicts of interest to declare.

Reduced-Intensity Unrelated Cord Blood Transplantation for Adult Patients with Severe Aplastic Anemia

Although unrelated cord blood transplantation (UCBT) has become a viable therapeutic option widely applicable for adult patients with hematological diseases, UCBT for severe aplastic anemia (SAA) remains to be controversial due to higher incidence of graft failure (GF) relative to the other stem cell sources. To evaluate the feasibility of UCBT for SAA, we retrospectively analyzed results for 11 adult patients with SAA who received first UCBT after reduced-intensity conditioning regimen (RI-UCBT) in Toranomon Hospital. Median age was 49 years (range, 20–70). Nine of them were non-responders to intensive immunosuppressive therapy and were multiply transfused, and two patients were fulminant type with no neutrophils in peripheral blood at diagnosis. The conditioning regimen consisted of fludarabine 125mg/m2, melphalan 80mg/m2, and 4 Gy of total body irradiation. Graft-versus-host disease prophylaxis was composed of cyclosporine alone (n=2), tacrolimus alone (n=2), and tacrolimus plus mycophenolate mofetil (n=7). Median total nucleated cell number and median CD34+ cell number were 2.65 × 107/kg (range, 1.83–4.39) and 0.70 × 105/kg (range, 0.27–1.52), respectively. Serological HLA disparities were as follows; 6/6 (n=3), 5/6 (n=2), and 4/6 (n=6). Ten of the 11 patients achieved primary neutrophil and platelet engraftment. Median time to an absolute neutrophil count > 0.5×109/liter and an unsupported platelet count > 20×109/liter were 18 days (range, 12–28) and 42.5 days (range, 26–64) respectively. All patients who achieved engraftment resulted in complete hematological recovery with complete donor chimerism, except for one patient who developed late GF at three years after UCBT. All 2 who experienced GF (1: primary GF, 1: late GF) were rescued by second RI-UCBT. Two of the 11 patients died from IPS (n=2), and remaining 9 patients are alive, having survived for 18.7 months (range, 2–71 months). Six out of 7 patients who survived more than 6 months were free from immunosuppressant. The probabilities of overall survival and event-free survival at 2 years after UCBT were 77.8% and 68.2%, respectively. Our results here strongly indicated feasibility and effectiveness of RI-UCBT for adult SAA patients with high engraftment rate and low treatment-related mortality. RI-UCBT could be considered as a viable therapeutic option for those who lack suitable HLA-matched sibling donors and failed immunosuppressive therapy.

High incidence of graft failure in unrelated cord blood transplantation using a reduced-intensity preparative regimen consisting of fludarabine and melphalan

High incidence of graft failure in unrelated cord blood transplantation using a reduced-intensity preparative regimen consisting of fludarabine and melphalan

BK Virus–Associated Nephropathy in Two Pediatric Kidney Recipients

Posttransplant renal dysfunction episodes can result from a variety of causes, including polyomavirus (BK virus)–associated nephropathy (PVAN). It is a well-recognized entity with a high incidence of graft failure. The delicate balance of viral infection and immune regulation in the transplant population would allow development of successful long-term strategies. In this presentation, we have described two PVAN cases of our institution and reviewed the literature.

Disparities of Minor Histocompatibility Antigens in Unrelated Allo-HCT.

Disparities of minor Histocompatibility antigens (mHag) have been considered as an important immunogenetic factor influencing immune responses following transplantation despite fully matched HLA of donor and recipient. The aim of our study was to answer whether mHag incompatibility may influence the outcome of allo-HCT. DNA samples from 92 unrelated donor/recipient pairs completely matched in HLA-A*,B*,C*,DRB1*,DQB1* alleles were collected in order to define minor Histocompatibility HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY genotypes with use of Dynal AllSet kits by PCR-SSP method. Unrelated allo-HCTs were performed in the Department of Hematology and BMT in Katowice, Poland, with use the same standard operating procedure from January 2004 until December 2006. Host versus Graft or Graft versus Host direction of immune responses in donor/recipient pairs was analyzed with use of the minor Histocompatibility Database of Leiden University Medical Center. We observed the impact of mHAg mismatches upon chronic GVHD, incidence of leukemia relapse and graft failure. Patients transplanted from donors with mHAg's incompatibility in GVH direction had higher probability of chronic GVHD in comparison to other pairs (54% vs 31%, p=0.07). This impact was most prominent for mismatched mHAgs with broad tissue distribution (62% vs 36%, p=0.04), especially HY (66% vs 38%, p=0.02). Opposite influence of HY mismatches in GVH direction was observed upon the probability of relapse, which was lower in the HY-mismatched than in HY-matched group (6% vs 23%, p=0.046). Two mHAgs with tissue distribution restricted to hematopoietic cells mismatched in HVG direction were associated with higher incidence of graft failure than in matched pairs: HA-1 (38% vs 12%, p=0.09) and HA-2 (50% vs 13%, p=0.09). Minor Histocompatibility typing of completely HLA matched patients helps to identify individuals who are at higher risk of cGVHD, leukemia relapse and graft failure, and thus supports precise matching of donor/recipient pairs for unrelated allo-HCT.

Multiple extensive coronary artery stenting: does it compromise future surgical revascularization?

In the era of percutaneous coronary intervention, surgeons are confronted with performing coronary artery bypass graft surgery on patients with previous balloon dilatation or stenting. This review evaluates the impact of previous percutaneous coronary intervention on patient survival and choice of optimal myocardial revascularization technique. Aggressive atherosclerosis has been remarked in patients complicated with intrastent stenosis. Moreover, bypass grafting with venous grafts has shown an extremely high incidence of graft failure in the restenosis population due to limited nitric oxide (a natural vasodilator) production of venous grafts. The challenge is to achieve complete revascularization in an unfavourable setting (greater co-morbidities, complex coronary lesions) with a greater risk of graft occlusion. The internal thoracic artery is the optimal graft for myocardial revascularization in patients with and without previous in-stent restenosis. Coronary artery reconstruction by exclusive internal thoracic artery grafting gives superior patency rates and clinical outcomes. It is the most appropriate approach for myocardial revascularization in these patients.

Developmental outcome in five children with Hurler syndrome after stem cell transplantation: a pilot study

Hurler syndrome (mucopolysaccharidosis type 1H; MPS1H) is a lysosomal storage disease caused by a deficiency of alpha-L-iduronidase activity. The natural course of this neurodegenerative disease inevitably leads to premature death within the first 10 years of life. Enzyme replacement therapy is effective in correcting the enzymatic deficiency of organs other than the central nervous system. Hematopoietic stem cell transplantation (SCT) is the only treatment known to prevent psychomotor deterioration. However, the classical transplantation protocols resulted in a high incidence of graft failure and regimen-related toxicity. Recently, we published a well-tolerated, fludarabine-based, radiation-free conditioning regimen for SCT in patients with Hurler syndrome. Here we report the developmental outcome (assessed by the Denver Developmental Screening Test before and yearly after SCT) of four females and one male with MPS1H (mean age at last follow-up 71mo, range 42-87mo) treated in accordance with this strategy. Mean age at SCT was 25 months (range 10-36mo). All children were engrafted and in ambulatory care. They all showed psychomotor development without neurodegeneration. In all patients, after SCT a regression of intracranial lesions could be seen that paralleled the psychomotor improvements. SCT led to a relative reduction of head circumference in all cases.

Successful Engraftment in Reduced-Intensity Cord Blood Transplantation (CBT) as a Salvage Therapy for Graft Failure After Primary CBT in Adults

Accumulating evidence strongly supports the efficacy of umbilical cord blood transplantation (CBT) in adults (1, 2). This now becomes a standard alternative to bone marrow or peripheral blood stem cell transplantation for patients who lack a human leukocyte antigen (HLA)-matched donor. However, surprisingly high incidence of graft failure (GF) after CBT (7–40%) has been reported (2–4). The second CBT could be a therapeutic strategy to rescue patients with GF, but very few cases of successful engraftment by the second CBT for patients with GF after primary CBT have been reported (4–6). In the past few years, we performed the second CBT in four cases with primary GF after CBT and all cases successfully achieved engraftment as summarized in Table 1. In these salvage CBTs, we paid attention to following three points. First, we tried to make a confirmation of GF and decision to perform the salvage CBT as quickly as possible. The confirmation of GF was made by no donor chimerism in bone marrow cells on day 28 or by no sign of hematopoietic recovery until day 35 (week 5) after primary CBT. Finally, the salvage CBT was performed before day 42 (week 6). The earlier application of salvage CBT while patients still have better performance status without infection or organ toxicities may improve the engraftment and survival.TABLE 1: Patient characteristicsSecond, considering toxicities of conditioning regimen used for primary CBT, reduced-intensity CBT was chosen for the second transplant to avoid regimen-related toxicity and mortality. Because strong immunosuppression has a clear advantage over engraftment, we used fludarabine-based preparative regimen. Subsequent conditioning therapy including fludarabine within a short duration after primary transplant and strong graft-versus-host disease (GVHD) prophylaxis could cause a high risk of infection, particularly cytomegalovirus (CMV) in CBT. However, only subclinical CMV infection occurred, which was well controllable with preemptive administration of ganciclovir. Acute GVHD was also mild. Third, to intensify the immunosuppression in combination with a key drug tacrolimus, we utilized mycophenolate mofetil (MMF) instead of methotrexate (MTX) which was used in the first CBT in cases 1, 2 and 3 for the following two reasons. MMF has been reported to cause lower incidence of mucositis compared with MTX (7). Although mechanism has not been elucidated, several reports have suggested that a GVHD prophylaxis regimen containing MMF after allogeneic transplantation is associated with faster engraftment (7–10). Our retrospective observation also shows the promotional effect of MMF in hematopoietic engraftment (data not shown), but further studies are necessary to decide the optimal dose of MMF for stem cell transplantation. We all have to recognize the fact that GF can possibly occur in approximately one third of adult CBT, particularly in the case of low transplant cell numbers. It would be important to make sure of a cord blood unit for salvage transplant as early as possible, and not to lose a chance to make a decision of the salvage CBT to avoid life-threatening complications. Further clinical studies are necessary to establish reduced-intensity CBT as a salvage therapy for primary GF. Yuriko Kawamori Kimikazu Yakushijin Atsuo Okamura Shinichiro Nishikawa Kentaro Minagawa Manabu Shimoyama Katsuya Yamamoto Yoshio Katayama Toshimitsu Matsui Hematology/Oncology Department of Medicine Kobe University Graduate School of Medicine Kobe, Japan

Bacterial Keratitis after Penetrating Keratoplasty: Incidence, Microbiological Profile, Graft Survival, and Visual Outcome

To determine the incidence, microbiological profile, graft survival, and factors influencing graft survival after the development of bacterial keratitis after penetrating keratoplasty (PK). Retrospective case series. One hundred two patients (102 eyes) treated at a single center during a 5-year period. Retrospective review of the medical records of every patient treated for culture-positive keratitis between January 1, 1998 and December 31, 2002 who previously had undergone penetrating keratoplasty at the King Khaled Eye Specialist Hospital. Graft survival and visual outcome. There were 2103 PKs performed and 102 (4.9%) cases of culture-positive keratitis during the study period. There were 168 bacterial isolates, of which 140 (83.3%) were gram positive, 28 (16.7%) were gram negative, and 1 (0.6%) was acid fast. Only 38 (37.3%) grafts remained clear after a mean follow-up of 985 days (range, 82-2284). The best graft survival was in eyes with PK for keratoconus (83.7%), whereas the poorest grat survival was for previously failed grafts (5.6%). By Kaplan-Meier analysis, there was an immediate steep decline in graft survival to 54.9%, followed by a slow decline to 47.2% by 1 year and 35.8% after 4 years. Factors associated with an increased risk of graft failure were the surgical indication for PK (P<0.001), increasing patient age (P = 0.004), smaller donor (P = 0.001) and recipient (P = 0.0003) graft size, history of previous microbial keratitis (P = 0.02) or endothelial rejection episodes (P = 0.02), and coexisting glaucoma (P = 0.001). The visual outcome was > or =20/40 in only 8 (8.2%) eyes and better than 20/200 in only 21 (21.6%) eyes. The development of bacterial keratitis after PK is a serious complication that is associated with a high incidence of graft failure and poor visual outcome.

CFU-GM Assay Can Be Predictive of Umbilical Cord Blood Engraftment.

Cord blood transplantation (CBT) has been considered a treatment modality to hematologic malignancies, marrow failure syndromes and genetic diseases. It has advantages such as immediate availability, lower risk of transmitting infections and higher tolerance to HLA disparities compared to bone marrow. The major drawbacks are slow hematopoietic recovery and a high incidence of graft failure or delayed engraftment, as a result of low stem progenitors (CD34+cells) yields. This study aimed at investigating if there was correlation between engraftment and number of total nucleated cells (TNC), number of CD34+ cells as well as number of granulocyte/monocyte colony forming units (CFU-GM) and erythroid burst forming units (BFU-E). Eighty four patients (age 0 to 55, M=7) with a variety of diseases (10 AML, 12 ALL, 31 Fanconi Anemia, 1 Hodgkin Lymphoma, 3 JMML, 3 Blackfan Diamond, 6 Wiskott Aldrich, 1 Krabbe Disease, 2 SAA, 4 CML, 3 Osteopetrosis, 3 SCID, 1 Diskeratosis Congenita, 1 Adrenoleukodystrophy, 1 Thalassemia Major, 1 Thrombocytopenia w/chromosome 7 monossomy) who underwent CBT were included in this study; 47.6% (40/84) of these patients had graft failure while 52.4% (44/84) showed successful engraftment. Regarding HLA-A, B and DRB1 matching, 20.2% (17/84) recipient/donor pairs were 6/6, 42.9% (36/84) were 5/6, 35.7% (30/84) were 4/6 and 1.2% (1/84) was 3/4. TNC and CD34+ cell counts in addition to hematopoeitic progenitor cells (CFU-GM and BFU-E) testing were performed in cord blood products after thawing and washing procedures. CD34+cells were analyzed by two color technique using FACS Calibur (San Jose, CA) and absolute counts were assessed by two-platform ISHAGE method. Colony assays for BFU-E and CFU-GM were performed by plating 3×104 mononuclear cells in methylcellulose medium with human recombinant cytokines (Methocult GF, Stem Cell Technologies); cultures were kept at 37°C in humidified incubator with 5% CO2 and after 14 days colonies were scored under an inverted microscope. Comparison of pre-thawing TNC [M=1.34×109(0.56–5.00)] and CD34+ [M=2.61×105/Kg (0.39–25.48)] cell counts, provided by cord blood banks, with post-thawing TNC [M=1.09×109(0.36–4.20)] and CD34+ [M=1.3×105/Kg(0.06–9.8)], performed by Wilcoxon signed rank test, showed a significant decrease in both cases (P<0.001). Descriptive statistics were tabulated separately for the number of TNC, number of CD34+ cells, numbers of CFU-GM and BFU-E colonies by whether patient engrafted or had graft failure, and comparison of the median cell counts between these two groups of patients was done by Wilcoxon Mann-Whitney rank sum test. TNC and CD34+ cell counts did not show significant difference between patients with graft failure [M=1.08×109(0.36–4.2) and M=1.28×105/Kg(0.09–9.8), respectively] and those who engrafted [M=1.12×109(0.46–2.49) and M=1.41×105/Kg(0.06–6.0), respectively]. Yet, the CFU-GM counts were significantly higher (P=0.005) for patients who engrafted [M=0.079×105(0.0017–0.75)] than for those who did not [M=0.04×105(0.0009–0.50)]. Although BFU-E counts did not differ with statistical significance between engrafted versus graft failure patients (P=0.059), higher counts could be observed in the group of patients who had successful engraftment. These data suggest that results of counts of CFU-GM colonies have a predictive value for engraftment in our center.

Umbilical cord blood transplantation

Over the past decade umbilical cord blood has been established as a viable source of hematopoietic stem cells for allogeneic transplantation. Early experience with umbilical cord blood transplantation (CBT) demonstrated a lower incidence of graft-versus-host disease even though the procedure was performed with HLA-disparate grafts. The overall outcome of CBT appears similar to that of allogeneic bone marrow transplantation. The expansion of the donor selection is particularly beneficial to ethnic minorities, whose representation in the marrow registries is relatively small. The major drawbacks of CBT are slow hematopoietic recovery and a high incidence of graft failure, as a result of a lower number of progenitors infused. This paper reviews the current results of CBT and ongoing investigations to increase its availability to a larger number of recipients.

Predictive value of intraoperative transit-time flow measurement for short-term graft patency in coronary surgery

The aim of this retrospective study was to evaluate the possibility to predict postoperative graft patency in coronary surgery by means of intraoperative transit-time flow measurement. Of 3567 patients submitted to isolated myocardial revascularization from June 1997 through June 2003, 157 (4.4%) underwent both intraoperative transit-time flow measurement and angiography at follow-up. Thirty-six have been revascularized on a beating heart. Three hundred four grafts, 227 arterial conduits, and 77 saphenous vein grafts were checked. No patients died, and none of them had an acute myocardial infarction within 12 months after the operation. After a mean of 6.7 +/- 4.8 months from the operation, 266 grafts (group A) were completely functioning, whereas 38 grafts (group B) had failed. The transit-time flow parameters recorded in the latter group had significantly lower mean flow and higher pulsatility index and percentage of backward flow values at both univariate and multivariate analysis. Moreover, mean flow values of 15 mL/min or less, pulsatility index values of 3.0 or greater, and percentage of backward flow values of 3.0% or greater were found to be independent variables for higher incidence of graft failure. Transit-time flow measurement represents a quick, easy, and reproducible method for intraoperative evaluation of graft function. The combination of the 3 major parameters (mean flow, pulsatility index, and percentage of backward flow) results in the chance to predict a graft failure (either anatomic or functional) within the first postoperative year.

Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome

Hurler syndrome (MPS 1H) is the severe form of mucopolysaccharidosis type 1 (MPS 1). Haematopoietic cell transplantation (HCT) is the treatment of choice, but carries a high incidence of graft failure and morbidity. The use of enzyme replacement therapy (ERT) might improve the clinical signs and symptoms before HCT, resulting in less transplantation-related complications. Moreover, clearance of glycosaminoglycans (GAG's) from the bone marrow might improve engraftment. Twenty-two patients with MPS 1H received one or more HCT procedures in combination with ERT. One patient with severe cardiomyopathy improved significantly after ERT. All children were in a relatively good clinical condition before HCT. Of patients 59, 82 and 86% were alive and engrafted after one, two and three HCT procedures, respectively. Two patients died after repetitive HCT. No serious ERT-infusion-related toxicity occurred. ERT with HCT was well tolerated. Neither a positive nor a negative effect on the number of patients who are alive and engrafted after receiving ERT before HCT as compared to a historic cohort was noted. However, patients in a poor clinical condition before HCT might benefit from ERT.

High incidence of graft failure and transplant related mortality (TRM) in 50 children receiving unrelated umbilical cord blood transplantation (UCBT) for non-malignant diseases

In countries with a high level of miscegenation, unrelated umbilical cord blood is a rapidly available source of hematopoietic stem cells for children with malignant and non-malignant diseases who lack a suitable HLA identical sibling. We report the results in 50 children with non-malignant diseases submitted to UCBT in our BMT center between 07/97 and 04/05. Median age: 6 years (20 days–14 years). Diseases: Fanconi Anemia (FA): 29 patients (pts); Primary Immunodeficiencies (PID): 10 pts (Wiskott Aldrich: 6 pts.

Umbilical cord blood transplantation

Over the past decade umbilical cord blood has been established as a viable source of hematopoietic stem cell for allogeneic transplantation. Early experience with umbilical cord blood transplantation (CBT) demonstrated a lower incidence of graft-versus-host disease even though the procedure was performed with HLA-disparate grafts. The overall outcome of CBT appears similar to that of allogeneic bone marrow transplant. The expansion of the donor selection is particularly beneficial to ethnic minorities, whose representation in the marrow registries is relatively small. The major drawbacks of CBT are slow hematopoietic recovery and a high incidence of graft failure, as a result of a lower number of progenitors infused. This paper reviews the current results of CBT and ongoing investigations to increase its availability to a larger number of recipients.

Outcome of Renal Transplantation in Patients with Non–Shiga Toxin–Associated Hemolytic Uremic Syndrome

More than 50% of patients with non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) progress to ESRD. Kidney transplant failure for disease recurrence is common; hence, whether renal transplantation is appropriate in this clinical setting remains a debated issue. The aim of this study was to identify possible prognostic factors for renal transplant outcome by focusing on specific genetic abnormalities associated with the disease. All articles in literature that describe renal transplant outcome in patients with ESRD secondary to non-Stx-HUS, genotyped for CFH, MCP, and IF mutations, were reviewed, and data of patients who were referred to the International Registry of Recurrent and Familial HUS/TTP and data from the Newcastle cohort were examined. This study confirmed that the overall outcome of kidney transplantation in patients with non-Stx-HUS is poor, with disease recurring in 60% of patients, 91.6% of whom developed graft failure. No clinical prognostic factor that could identify patients who were at high risk for graft failure was found. The presence of a factor H (CFH) mutation was associated with a high incidence of graft failure (77.8 versus 54.9% in patients without CFH mutation). Similar results were seen in patients with a factor I (IF) mutation. In contrast, graft outcome was favorable in all patients who carried a membrane co-factor protein (MCP) mutation. Patients with non-Stx-HUS should undergo genotyping before renal transplantation to help predict the risk for graft failure. It is debatable whether a kidney transplant should be recommended for patients with CFH or IF mutation. Reasonably, patients with an MCP mutation can undergo a kidney transplant without risk for recurrence.

Impact of pre-transplant anaemia correction and erythropoietin resistance on long-term graft survival

This study investigated whether recombinant human erythropoietin (rHuEPO)-hyporesponsive anaemia before transplantation is associated with a poorer graft outcome and lower patient survival. A total of 15,051 kidney transplant recipients, with a minimum follow-up of 1 year, were stratified as either rHuEPO hyporesponsive or rHuEPO responsive (using a threshold rHuEPO-treated haemoglobin level of 11 g/dl). They were followed for a median of 24 months. Outcomes included times from transplantation to graft failure (including patient death), return to dialysis or pre-emptive re-transplantation, and death with a functioning graft. The cumulative incidence of graft failure was 50% for rHuEPO-hyporesponsive patients, compared with 41.7% for rHuEPO responders (P = 0.0091). Among rHuEPO-hyporesponsive patients, 41.7% returned to dialysis or underwent a pre-emptive re-transplantation, compared with 32% of rHuEPO responders (P = 0.0091). Death with a functioning graft occurred in 16.9% of rHuEPO-hyporesponsive and in 15% of rHuEPO-responsive patients (P = 0.3949). The results showed higher mortality and higher incidence of graft failure at 5 years for rHuEPO-hyporesponsive patients. It is unclear whether anaemia treatment per se or treatment of more severe co-morbidity resulting in hyporesponsiveness to anaemia treatment may be causally linked to reduced renal transplant outcomes.

Femoral vein transposition for arteriovenous hemodialysis access: Improved patient selection and intraoperative measures reduce postoperative ischemia

Construction of prosthetic arteriovenous access for hemodialysis in the thigh results in a high incidence of graft failure and infection. Autogenous femoral artery-common femoral thigh transposition (transposed femoral vein [tFV]) arteriovenous accesses have superior patency, but our previous report documented a high incidence of ischemic events requiring secondary surgical intervention. Recent results of improved patient selection and intraoperative maneuvers to reduce ischemia are unknown. During a 6-year period eight children (mean age, 13.3 years) and 46 adults (mean age, 52.3 years; 27 female, 19 male) underwent construction of 55 tFV thigh accesses for hemodialysis access. Adult patients were divided into groups I and II on the basis of the introduction of specific strategies to reduce the incidence of ischemic complications. In the cohort of children, steal prophylaxis included one banded femoral vein, three tapered femoral veins, two distal femoral artery pressure measurements taken before and after access construction (mean ratio, 0.70), and two closed anterior and superficial posterior compartment fasciotomies. Of the first 25 accesses in adults (group I, mean age, 55.9 years), 10 had access banding (six at the initial procedure and four in the immediate postoperative period to treat ischemia). Of the second 22 accesses (group II, mean age, 48.2 years), steal prophylaxis included 14 tapered femoral veins, 6 distal femoral artery pressure measurements (mean ratio, 0.76; range, 0.62 to 0.86), and 1 fasciotomy. Patients with significant distal occlusive disease were not offered a tFV access in the time frame of group II. Eight accesses in children had 100% primary functional patency at 2 years, with no reoperations for ischemia. Nine group I adult patients underwent remedial procedures to correct distal ischemia. No adult patient in group II required a remedial procedure to correct ischemia. Groups I and II 2-year secondary functional access patency was 87% and 94%, respectively. There were no access infections in either group. Femoral vein tapering significantly reduced the need for remedial correction of ischemia ( P = .03). Improved patient selection and selective intraoperative femoral vein tapering eliminated remedial procedures to correct ischemia in patients undergoing tFV access. Patency rates were excellent despite the liberal use of vein tapering. Transposed FV access should be considered for good risk individuals undergoing their first lower extremity access.