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Background: Many pediatric transplant (TX) centers routinely monitor Epstein-Barr (EB) viral load (VL) by real time quantitative PCR and intervene to prevent post-transplant lymphoproliferative disorder (PTLD). Some children develop asymptomatic persistent VL (PVL). Outcome of different interventions in preventing PTLD and other undesired effects on acute rejection (AR), graft failure (GF) and function amongst children with asymptomatic PVL is not known. Methods: NAPRTCS centers invited to enter data on children with asymptomatic PVL (≥ 6 months) into the EB VL registry. Comparison group included children into the NAPRTCS TX arm during the same period without PVL or VL monitoring. EB VL were arbitrarily divided into low (1-10), medium (>10-100) and high (>100times detection limit for the center) ratio. Results: Of 645 children (18 centers), 85 (13.2%) developed onset of PVL at a mean of 6.4 ± 6.3 months post-TX. PVL children were more likely to be younger (< 5 years) at TX and less likely to be African-American and majority (75.3%) was mismatched for EBV (donor EBV IgG positive and recipient negative). Thymoglobulin induction was used in 29.4% children with PVL versus 37% in controls (p=ns). PTLD developed in 7/85 (8.2%) children with PVL versus 5/560 (0.9%) controls (p < 0.0001). EB VL ratios were not different in those with and without PTLD. EB PVL as time varying covariate did not affect patient survival, GF and AR (HR, 0.85, 0.53 and 0.99). The change in GFR overtime in children with PVL was comparable to controls. Conclusion: Children with PVL (actual load not predictive) are at increased risk for PTLD, but not for AR, death, GF or loss of graft function.

This review discusses unique aspects of kidney transplantation in children that necessitate specialized approaches and have resulted in clinical advances so that kidney transplantations in young children have higher success rates than in any other age group.

Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid-free (SF; n = 60) or steroid-based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow-up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody-mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

The incidence of developing circulating anti-human leukocyte antigen antibodies and the kinetics of T cell depletion and recovery among pediatric renal transplant recipients who receive alemtuzumab induction therapy are unknown. In a collaborative endeavor to minimize maintenance immunosuppression in pediatric renal transplant recipients, we enrolled 35 participants from four centers and treated them with alemtuzumab induction therapy and a steroid-free, calcineurin-inhibitor-withdrawal maintenance regimen. At 3 months after transplant, there was greater depletion of CD4(+) than CD8(+) T cells within the total, naive, memory, and effector memory subsets, although depletion of the central memory subset was similar for CD4(+) and CD8(+) cells. Although CD8(+) T cells recovered faster than CD4(+) subsets overall, they failed to return to pretransplant levels by 24 months after transplant. There was no evidence for greater recovery of either CD4(+) or CD8(+) memory cells than naïve cells. Alemtuzumab relatively spared CD4(+)CD25(+)FoxP3(+) regulatory T cells, resulting in a rise in their numbers relative to total CD4(+) cells and a ratio that remained at least at pretransplant levels throughout the study period. Seven participants (20%) developed anti-human leukocyte antigen antibodies without adversely affecting allograft function or histology on 2-year biopsies. Long-term follow-up is underway to assess the potential benefits of this regimen in children.

Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that ∼30-40% of human CD25(hi) FOXP3(+) CD4(+) Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-γ production were significantly higher using CXCR3-depleted versus undepleted responders in the mixed lymphocyte reaction, as well as following mitogen-dependent activation of T cells. Using microfluidics, we also found that CXCR3 was functional on CXCR3(pos) Tregs, in as much as chemotaxis and directional persistence towards interferon-γ-inducible protein of 10 kDa (IP-10) was significantly greater for CXCR3(pos) than CXCR3(neg) Tregs. Following activation, CXCR3-expressing CD4(+) Tregs were maintained in vitro in cell culture in the presence of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and we detected higher numbers of circulating CXCR3(+) FOXP3(+) T cells in adult and pediatric recipients of renal transplants who were treated with mTOR-inhibitor immunosuppressive therapy. Collectively, these results demonstrate that the peripheral homing receptor CXCR3 is expressed on subset(s) of circulating human Tregs and suggest a role for CXCR3 in their recruitment into peripheral sites of inflammation.

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children agedor =5 versus those12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient ageor =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

Chronic renal dysfunction may develop after pediatric heart transplantation (PHTx). We examined the incidence of end-stage renal disease (ESRD) and chronic renal insufficiency (CRI) after PHTx, the associated pre-transplant patient characteristics, and impact of renal disease on survival.Data sources included the Scientific Registry of Transplant Recipients, Centers for Medicare and Medicaid Services and the Social Security Death Master File. All PHTx recipients (age18 years) in the USA from 1990 to 1999 who survived1 year were included. ESRD was defined as long-term dialysis and/or kidney transplant. CRI was defined as creatinine2.5 mg/dl, including those with ESRD. Relationships between pre-transplant characteristics and time to ESRD and CRI were analyzed using Cox proportional hazards models. The effect of renal disease on survival was analyzed using time-dependent Cox models.During the mean follow-up of 7 years (range 1 to 14 years), 61 of 2,032 (3%) PHTxs developed ESRD. Ten-year actuarial risks for ESRD and CRI were 4.3% and 11.8%, respectively. In a multivariate analysis, significant risk factors for ESRD were: hypertrophic cardiomyopathy; African-American race; intensive care unit (ICU) stay or extracorporeal membrane oxygenation (ECMO) at time of transplant; and pre-transplant diabetes. Risk factors for CRI were: pre-transplant dialysis; hypertrophic cardiomyopathy; African-American race; and previous transplant. Adjusted risk of death in those who developed CRI was 9-fold higher than in those who did not (p0.0001).After PHTx there is an increasing risk for CRI and ESRD over time. Recipients with the characteristics identified in this study may be at greater risk. Development of renal disease significantly increases the risk of post-transplant mortality.

We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C(max)), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m(2), and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r(2) = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI.

Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone, mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr of follow-up. One enrolled patient did not receive the transplant because of a donor problem, eight terminated because of one or more rejection episodes, four terminated because of adverse events, and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other as a result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend to a mean of 70 ml/min thereafter. Early surveillance graft biopsies frequently showed focal interstitial mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared without treatment. Anti-HLA class I and II antibodies were detected in three patients before transplantation, and all three had acute rejections, including the two patients who lost their grafts. De novo anti-HLA Ab production occurred in only one patient after transplantation. There were two episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which developed after the patient had been terminated from the study. It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation. However, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.

Graft thrombosis is the most common cause of first year graft failure in pediatric renal transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database was analyzed for cases of graft failure due to thrombosis among patients transplanted from 1998 to 2004. The impact of interleukin-2 (IL-2) receptor antagonists as induction therapy was determined. There were a total of 51 graft failures due to thrombosis among the 2750 reported renal transplants (1.85%) (95% CI (1.39%, 2.41%)). This represents the most common cause of graft loss during the first year post-transplant accounting for 35% of first year losses and 18% of all graft losses. The incidence of thrombosis among patients who received IL-2 receptor antibodies was 1.07% (12/1126) compared to 2.40% (39/1624) among patients who did not (OR 0.44, 95% CI 0.23, 0.84, p = 0.014). Use of IL-2 receptor blockade was the only significant prognostic factor in a multivariate model with previously identified risk factors. Analysis of NAPRTCS data found that the use of IL-2 receptor antibodies as induction therapy is associated with a significantly decreased risk of graft failure due to thrombosis. This provocative finding requires further investigation to determine whether thrombotic failure can be decreased by this therapeutic strategy.

Acute rejection leading to renal graft failure is more frequent among children. In patients treated with T cell antibody induction, retrospective data from the pediatric registry show a 22% reduction in the risk of graft failure. We conducted a randomized trial (n = 287) using OKT3 mAbs in one (OKT3) arm and intravenous cyclosporine in the other arm (CYS). Maintenance therapy consisted of randomized, double blind Sandimmune® or Neoral® together with prednisone and either azathioprine (AZA) or mycophenolate mofetil (MMF). Morbidity, mortality, rejection rates and adverse reactions in the two study arms were similar. Through 4 yr, graft failure was 27% in OKT3 and 19% in CYS (p = 0.15). One-year graft survival was 89.1% in OKT3 and 89.2% in CYS (p = .19). In multivariate analysis, OKT3 had a numerically inferior graft survival (RR = 1.4, CI 0.8–2.2, p = 0.22). In OKT3 graft survival was inferior for children aged 6 yr or younger. Our trial demonstrates that the incidence of acute rejection or graft failure in pediatric patients is not improved by OKT3 induction therapy relative to cyclosporine induction.

Kidney transplantation from live donors achieves an excellent outcome regardless of human leukocyte antigen (HLA) mismatch. This development has expanded the opportunity of kidney transplantation from unrelated live donors. Nevertheless, the hazard of hyperacute rejection has usually precluded the transplantation of a kidney from a live donor to a potential recipient who is incompatible by ABO blood type or HLA antibody crossmatch reactivity. Region 1 of the United Network for Organ Sharing (UNOS) has devised an alternative system of kidney transplantation that would enable either a simultaneous exchange between live donors (a paired exchange), or a live donor/deceased donor exchange to incompatible recipients who are waiting on the list (a live donor/list exchange). This Regional system of exchange has derived the benefit of live donation, avoided the risk of ABO or crossmatch incompatibility, and yielded an additional donor source for patients awaiting a deceased donor kidney. Despite the initial disadvantage to the list of patients awaiting an O blood type kidney, as every paired exchange transplant removes a patient from the waiting list, it also avoids the incompatible recipient from eventually having to go on the list. Thus, this approach also increases access to deceased donor kidneys for the remaining candidates on the list.

SRL is an mTOR inhibitor that provides several advantages over CNI immunosuppressive protocols. mTOR inhibitors such as SRL have been shown to result in less renal and gastrointestinal toxicity, and beneficial effects on countering vascular proliferation in comparison with 4 CNI such as cyclosporine and tacrolimus. Complications of SRL include hyperlipidemia that often requires co-therapy with lipid-lowering agents, and transient thrombocytopenia. Current SRL use in children is based mostly on extrapolation of PK data in adult transplant recipients and single dose PK data in children on hemodialysis. One study of adult transplant recipients showed that the SRL T1/2 is 62 ± 16 h (1). Another study of single dose SRL in 16 stable, adult renal transplant recipients showed that the elimination T1/2 ranged from 43.8 to 86.5 h, with a mean of 56.9 h (2). A single dose PK study in uremic children on hemodialysis showed similar T1/2 values (70.5 ± 40 h in children and 55.3 ± 18 h in adolescents) (3). However, these data do not reflect steady state SRL PK in stable, pediatric renal transplant recipients. Previously, young children were reported to have poor short and long-term graft survival. Proposed reasons for this poor survival included an hypothesized heightened immune response, especially in infants (4, 5). However, other causes were likely more important. Children are known to have higher rates of drug metabolism, particularly with respect to key cytochrome enzymes compared with adults (6–12). Faster drug metabolism is very likely the reason why cyclosporine T1/2 is notoriously shorter in children compared with adults. One study determined that cyclosporine T1/2 was 9.3 h in children, compared with 16–27 h in adults (13). Therefore, it is possible that lack of pediatric-specific PK information previously led to insufficient provision of these drugs to children. Thus, suboptimal immunosuppression, rather than an inherent immune hyper-responsiveness, may have been the cause of higher rejection rates previously seen in young children. Improved age-specific dosing, therefore, may have been instrumental in the recently observed improved outcomes in children (14, 15). We have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients, including SRL PK studies at 1 and 3 months after transplantation. The goal of this study is to assess SRL PK in children on a CNI-free protocol, and to determine whether these pediatric renal transplant recipients require different doses or dosing schedules of SRL.

The North American Pediatric Renal Transplant Cooperative Study has collected clinical information on children undergoing a renal transplantation since 1987. This cooperative group now includes over 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. This report covers the years from 1987 through 2001 and includes data on 7545 renal transplants in 6878 patients. This report demonstrates changing trends in many areas of pediatric transplantation including increasing numbers of African American and Hispanic children receiving transplantation, remarkable improvements in the rate of acute rejection, rejection reversal, and short- and long-term allograft survival. In the most recent cohorts of patients, we now see that 1-yr allograft survival is no different in cadaver donor compared to living donor recipients and in infants compared to all other age groups. However, this analysis also reveals areas of continued challenges including inferior outcomes in African American and adolescent populations, chronic rejection, and the adverse effects of immunosuppression.

In March, 2002, over 100 members of the transplant community assembled in Philadelphia for a meeting designed to address problems associated with the growing number of patients seeking kidney transplantation and added to the waiting list each year. The meeting included representatives of nine US organizations with interests in these issues. Participants divided into work groups addressing access to the waiting list, assigning priority on the list, list management, and identifying appropriate candidates for expanded criteria donor kidneys. Each work group outlined problems and potential remedies within each area. This report summarized the issues and recommendations regarding the waiting list for kidney transplantation addressed in the Philadelphia meeting.

Recent evidence suggests that a population of professional regulatory cells, which limit immune responsiveness, exist in rodents and healthy human subjects. However, their role in disease states remains unclear. A proportion of renal transplant recipients do not demonstrate in vitro reactivity toward their mismatched donor-derived HLA-DR antigens; it was therefore hypothesized that this may be due to such regulatory cells. A cohort of 23 renal transplant recipients was studied at a single institution. In patients with no history of acute rejection, 6 (40%) of 15 demonstrated regulation toward the mismatched HLA-DR allopeptides by CD25(+) cells. By contrast, only one (12.5%) in eight of those with a history of acute rejection demonstrated regulation. Interestingly, if the patient assays were stratified according to initial in vitro immune responsiveness toward the mismatched allopeptides, 8 (47.1%) of 17 of patient assays with low allopeptide responsiveness (alloreactive T cell frequencies less than 60/million) demonstrated regulation of indirect pathway alloresponses by CD25(+) cells, whereas 0 of 8 with higher responses (frequencies greater than 60/million) demonstrated no such regulation (P < 0.05 by chi(2) test). The regulatory cells are present in the circulation as early as 3 mo after transplantation and persist for a number of years, despite conventional immunosuppression. Furthermore, induction treatment with anti-IL-2R mAb did not prevent the development of these regulatory CD25(+) cells. Data from two patients suggest that these cells may also play a role in preventing epitope shifting, implicated in the ongoing immune activation contributing to chronic rejection, and that loss of regulation in a given patient may precede an episode of rejection.

Graft thrombosis is a common cause of graft failure in pediatric renal transplantation. Several previous studies, including a North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) review of pretransplant dialysis status and graft outcomes, have described a potential correlation of peritoneal dialysis (PD) and graft thrombosis. This issue is of particular concern for pediatric transplant programs as more than 65% of children with end stage renal disease are treated with PD. We reviewed 7247 pediatric renal transplants performed between 1987 and 2001. Thrombosis was the cause of graft loss in 2.7% (199) of all the transplants performed. Among failed transplants, thrombosis was the third most common cause of graft loss in both index (11.6%) and subsequent transplants (14.5%). Thrombosis becomes the most common cause of graft failure (21%, 61/294) if one looks at transplants in the later cohort, from 1996 to 2001. This change is primarily because of a decrease in the incidence of acute rejection. In the PD group, 3.4% of all grafts were lost as a result of thrombosis. This compares with 1.9% in the hemodialysis group, 2.4% in the pre-emptive transplant group, and 4.1% among patients who received both dialysis modalities. There was a statistically significant difference in thrombosis failure risk in the different dialysis groups (p = 0.005) with those who received only peritoneal dialysis having the highest risk. Additional significant risk factors for graft thrombosis included; cadaver donor source (p 24 h (p 5 pretransplant blood transfusions (p = 0.02). Using stepwise proportional hazards modeling, only pretransplant peritoneal dialysis, >24 h cold ischemia time, prior transplant, and donor age

The short-term success rate of cadaveric renal transplants has improved dramatically during the past decade. In 1990, one-year graft survival rates were about 70%; by 2000, they were greater than 90% (United States Renal Data System, 2001). Unfortunately, as transplantation has become more

Tacrolimus (FK506) and mycophenolate mofetil (MMF) have been reported to increase PTLD risk. The NAPRTCS registry database now has several years of data on FK506 and MMF use in pediatric kidney transplantation. We analyzed the data registry to determine if the risk of PTLD was enhanced by the use of MMF or tacrolimus in initial immunosuppression. Data on day 30 therapy in the PTLD group were compared to corresponding data in patients who did not develop PTLD. Data were analyzed using SAS software and a log-rank test for significance. As of October 2000, there were 108 cases of PTLD in 6720 total transplants(1.60%). The use of MMF at day 30 was not a significant risk factor (0. 78% PTLD rate vs. 1.78% in cohort, RR = 1.05, p = 0.89). The relationship of FK506 with PTLD was linked to transplant era, 1987-95 or 1996-2000. In the earlier era, use of FK506 at day 30 was associated with PTLD (seen in 7/15 patients given FK506, RR = 47.7, p < 0.001). However, in the more recent era, there was no such significant association (seen in 3/313 patients given FK506, RR = 1.28, p = 0.692). There have been no cases of PTLD in 197 patients who received both FK506 and MMF at day 30. We conclude that FK506 and MMF use are not currently associated with increased risk of PTLD in pediatric kidney transplants.

Background. The success of kidney transplantation from a genetically unrelated living spouse or friend has influenced transplant physicians to consider the requests of individuals wishing to volunteer to be a kidney donor who have no intended recipient specified. Representatives of the transplant community gathered in Boston, MA, on May 31, 2001, to deliberate on the experience of live kidney donation from such volunteers, currently termed nondirected donors (NDD). Objective of Conference Participants. The objective of the conference was to recommend ethical and practice guidelines for health care professionals considering the transplantation of a kidney from a live NDD. Conference Participants. This conference was convened under the sponsorship of The National Kidney Foundation, with representation from The American Society of Transplantation and The American Society of Transplant Surgeons, The American Society of Nephrology, The United Resource Networks, The United Network for Organ Sharing, The Association of Organ Procurement Organizations, The National Institutes of Health, and The Division of Transplantation of the Health Resources and Services Administration (see Appendix). Conference Report. The suggested content of screening interviews, which provide information regarding the donation process, elicits pertinent medical and psychosocial history, and assesses NDD motivation are presented in this report. Approaches to identifying the center that would evaluate the suitability of the NDD, to performing the kidney recovery, and to selecting the NDD recipient are also proposed. Other ethical issues such as the use of prisoners as an NDD, compensation for the NDD, media involvement, and communication between the NDD and recipient are discussed. Conclusion. The willingness of health care professionals to consider NDD volunteers is driven by the compelling need to provide organs for an ever-expanding list of patients awaiting a kidney transplant. However, the psychological impact and emotional reward of donation has yet to be determined for NDD who may not have any relationship to the recipient or knowledge of the recipient’s outcome. Transplant centers that accept NDD should document an informed consent process that details donor risks, assures donor safety, and determines that the goals and expectations of the NDD and the recipient can be realized.

Maple syrup urine disease (MSUD) is an inborn error of metabolism stemming from a deficiency in 2-ketoacid dehydrogenase and resulting in the systemic accumulation of branched chain amino acids (BCAAs). Affected children may suffer profound developmental and cognitive impairment from exposure to high levels of BCAA and their associated neurotoxic metabolites. Endogenous renal clearance of BCAA is limited and several therapeutic modalities including intensive nutritional regimens, exchange transfusions, peritoneal dialysis, and continuous hemofiltration have been utilized in neonates with MSUD, all of which have had varying success in reducing systemic BCAA levels. In this report, a symptomatic 7-day-old 3-kg neonate with MSUD underwent treatment with a combination of early hemodialysis and aggressive enteral feedings of a metabolically appropriate formula. This approach results in a 75% reduction of systemic toxin levels within 3 h. When compared to other reported modalities of therapy for symptomatic neonates with MSUD, this approach appears to be most efficacious. Moreover, by minimizing the amount of time that an affected neonate is exposed to neurotoxic levels of BCAAs, long-term developmental and cognitive capabilities may be preserved.

A 13-year-old girl who recently developed hypertension was diagnosed to have an occluded right renal branch artery and was treated successfully with percutaneous transluminal angioplasty (PTA). To our knowledge, PTA has not been reported as a treatment for totally occluded renal branch arteries, and there is no data available regarding the success rate and possible complications.

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

For the first time in nearly 30 years, the Centers for Medicare and Medicaid Services (CMS) will implement a new payment system for dialysis patients. Since 1983, Medicare has reimbursed each dialysis session with a prospective payment—known as the composite rate—designed to cover the cost of center or home dialysis.1 Since implementation of the composite rate, however, new therapies—including erythropoietin, vitamin D, and iron—have emerged as new additional costs for standard dialysis care. These therapies are reimbursed separately from the composite rate and now compose approximately 40% of the total Medicare payment for each dialysis treatment.2 To improve the efficiency and flexibility of the ESRD Program, the Medicare Improvements for Patients and Providers Act (MIPPA) of 2008 mandated implementation of a comprehensive, case mix–adjusted, bundled-rate payment system for ESRD that includes therapies currently reimbursed outside the composite rate.3 The ESRD Prospective Payment System will be phased in on January 1, 2011, and fully implemented by 2014. Although MIPPA outlines the basic approach to bundling, the legislation grants CMS authority to finalize the components of the bundle and generate a detailed implementation plan. In September 2009, CMS released for public comment a proposed rule on ESRD bundling and is expected to issue a final rule on ESRD bundling in 2010. In addition, CMS is projected to release a proposed rule on a quality improvement program for ESRD care. Given the monumental significance of the new payment system, the American Society of Nephrology (ASN) formed an ESRD task force to assess and respond comprehensively to the proposed rule changes. Eight ASN members from diverse specialties and practice settings served on this task force, including early-career and established nephrologists as well as ASN policy staff. ASN's foremost concerns relate to preservation of patient access to optimal dialysis care and related …

McGuire MM, Jones BA, Hull MA, Misra MV, Smithers CJ, Feins NR, Jenkins RL, Lillehei CW, Harmon WE, Jonas MM, Kim HB. Combined en bloc liver–double kidney transplantation in an infant with IVC thrombosis. Pediatr Transplantation 2011: 15: E142–E144. © 2010 John Wiley & Sons A/S. Abstract: We report a case of a pediatric en bloc liver-double kidney transplant in a patient with IVC thrombosis below the renal veins. The patient is an 11-month-old girl diagnosed with congenital nephrotic syndrome at two months of age. Multifocal liver masses were identified on routine ultrasound at eight months of age. Alpha fetoprotein level was 55 319. Biopsy confirmed hepatoblastoma. CT scan confirmed multiple lesions in both lobes, which would require liver transplantation for resection. She was also found to have thrombosis of her infrarenal IVC secondary to multiple central lines. She was listed for combined liver–kidney transplant and began chemotherapy. After four cycles of chemotherapy, she underwent bilateral nephrectomies followed by a combined en bloc liver-double kidney transplant from a size matched donor. In order to provide adequate venous outflow from the kidneys in the absence of a recipient infrarenal IVC, the donor liver and kidneys were procured en bloc with a common arterial inflow via the infrarenal aorta and common outflow via the suprahepatic IVC. Kidney transplantation in the absence of adequate recipient venous drainage may require unusual vascular reconstruction techniques. This case demonstrates a novel approach in patients who may require combined liver–kidney transplantation.

Objective To recommend practice guidelines for transplant physicians, primary care providers, health care planners, and all those who are concerned about the well-being of the live organ donor. Participants An executive group representing the National Kidney Foundation, and the American Societies of Transplantation, Transplant Surgeons, and Nephrology formed a steering committee of 12 members to evaluate current practices of living donor transplantation of the kidney, pancreas, liver, intestine, and lung. The steering committee subsequently assembled more than 100 representatives of the transplant community (physicians, nurses, ethicists, psychologists, lawyers, scientists, social workers, transplant recipients, and living donors) at a national conference held June 1-2, 2000, in Kansas City, Mo. Consensus process Attendees participated in 7 assigned work groups. Three were organ specific (lung, liver, and kidney) and 4 were focused on social and ethical concerns (informed consent, donor source, psychosocial issues, and live organ donor registry). Work groups' deliberations were structured by a series of questions developed by the steering committee. Each work group presented its deliberations to an open plenary session of all attendees. This information was stored and shaped into a statement circulated electronically to all attendees for their comments, and finally approved by the steering committee for publication. The term consensus is not meant to convey universal agreement of the participants. The statement identifies issues of controversy; however, the wording of the entire statement is a consensus by approval of all attendees. Conclusion The person who gives consent to be a live organ donor should be competent, willing to donate, free from coercion, medically and psychosocially suitable, fully informed of the risks and benefits as a donor, and fully informed of the risks, benefits, and alternative treatment available to the recipient. The benefits to both donor and recipient must outweigh the risks associated with the donation and transplantation of the living donor organ.

In an attempt to identify potential markers of steroid-resistance in focal segmental glomerulosclerosis (FSGS) we evaluated intra-graft gene expression of IkappaBalpha, nuclear factor-kappaB (NF-kappaB), and angiotensinogen in 60 biopsies from 27 pediatric renal transplant recipients. Intra-graft NF-kappaB expression was significantly elevated in recurrent FSGS (R-FSGS) (218.3 + 55.6 ag/fg versus NON-FSGS 121.1 + 19.9, P=0.04) but not in acute rejection. NF-kappaB:IkappaBalpha ratios were higher in cadaveric donor versus living related donor recipients (15.7 + 2.8 vs. 8.8 + 1.3, respectively, P=0.015), and in African-American versus Caucasian recipients (15.6 + 2.9 vs. 9.1 + 1.3, respectively, P=0.03). Intra-graft angiotensinogen gene expression was significantly elevated in R-FSGS (30.5 + 8.8 ag/fg R-FSGS vs. 16.0 + 4.7 NON-FSGS, P=0.009). We conclude that increased NF-kappaB and angiotensinogen gene expression are associated with R-FSGS. Increased NF-kappaB:IkappaBalpha ratios are associated with cadaveric donor recipients and African-American race.

Many complications after renal transplantation can be prevented if they are detected early. Guidelines have been developed for the prevention of diseases in the general popu- lation, but there are no comprehensive guidelines for the pre- vention of diseases and complications after renal transplanta- tion. Therefore, the Clinical Practice Guidelines Committee of the American Society of Transplantation developed these guidelines to help physicians and other health care workers provide optimal care for renal transplant recipients. The guide- lines are also intended to indirectly help patients receive the access to care that they need to ensure long-term allograft survival, by attempting to systematically define what that care encompasses. The guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpa- tient screening for and prevention of diseases and complica- tions that commonly occur after renal transplantation. They do not cover the diagnosis and treatment of diseases and compli- cations after they become manifest, and they do not cover the pretransplant evaluation of renal transplant candidates. The guidelines are comprehensive, but they do not pretend to cover every aspect of care. As much as possible, the guidelines are evidence-based, and each recommendation has been given a subjective grade to indicate the strength of evidence that sup- ports the recommendation. It is hoped that these guidelines will provide a framework for additional discussion and research that will improve the care of renal transplant recipients.

Background. We report the consequences of a novel kidney allocation system on access of non-Caucasians (NC) to kidney transplantation. This new plan has provided a balance of allocation determinants between time waiting, HLA match, and geography (population density between donor and recipient center). Methods. Three sequential systems of regional allocation were analyzed: period I (September 1994 to September 1996), period II (September 1996 to November 1997), and period III (December 1997 to March 1 1999). Periods II and III are reflective of the new allocation plan. Results. During periods II and III, the NC rate of kidney transplantation increased closer to the NC proportion on the wait list, comparatively exceeding the national UNOS data. There was no statistical difference in regional mean wait time between Caucasian and NC. Improvements in access to transplantation for NCs between period I and periods II and III appear to be related to changes in geographic allocation weight from local unit to population density points, to the inclusion of the entire region in the plan, and to the deletion of intermediate degrees of B/DR mismatching in the revised plan. Despite the increased proportion of NCs on the wait list from period I to period III, the percentage difference between the proportion of NCs waiting on the list and the proportion NCs receiving a transplant fell from 7.8% to 4.9%. Conclusions. These data demonstrate that this new allocation plan was associated with improved access of minority candidates to transplantation. The broadening of geographic allocation and the alteration of HLA points appear to permit a more favorable opportunity for renal transplantation to NC candidates.

We define delayed graft function (DGF) as the need for dialysis during the first post-transplant week. We analyzed 5272 transplants, of which 2486 were of living donor (LD) and 2786 were of cadaver donor (CD) origin. Twelve per cent (620/5272) of all patients developed DGF. Donor specific rates were 5.6% for LD and 19.1% for CD patients. Factors predictive of DGF in CD patients were: African-American race (25%), prolonged cold ischemia (24%), absence of T-cell induction antibody therapy and absence of HLA-DR matching. The relative risk (RR) for graft failure due to DGF was 6.02 (p < 0.001) in LD patients and 2.58 (p < 0.001) for CD recipients. Two-year graft survival (GS) in LD patients without DGF was 89.6%, compared to 41.6% for those with DGF (p < 0.001); in CD patients it was 80.2% and 49.5%, respectively (p < 0.001). Censoring for primary non-function, GS for LD patients with a functioning graft at 30 d post-transplant and no DGF was 91.5%, compared to 70.1% for those with DGF (p < 0.001); GS for CD patients was 83.8% and 68.7%, respectively (p < 0.001). However, when patients whose grafts had failed during the first year were censored no differences in GS were noted between patients with and without DGF for either LD or CD recipients. To determine whether DGF acts as an independent risk factor for graft failure, patients were segregated into four groups: rejection with DGF; rejection without DGF; DGF without rejection; and no DGF, no rejection. When these groups were compared DGF emerged as an independent risk factor for graft failure. This large study reviewing pediatric renal transplantation over 10 yr clearly delineates the role of DGF as a major risk factor for graft failure.

The development of organ transplantation as a widely available and clinically effective therapy has provided an enormous benefit for the care of patients with end-stage renal disease (ESRD). One-year cadaver donor graft survival rates have improved from 52% to nearly 90% between 1977 and 1998 ([1][1

Efficient and safe heparin anticoagulation has remained a problem for continuous renal replacement therapies and intermittent hemodialysis for patients with acute renal failure. To make heparin therapy safer for the patient with acute renal failure at high risk of bleeding, we have proposed regional heparinization of the circuit via an immobilized heparinase I filter. This study tested a device based on Taylor-Couette flow and simultaneous separation/reaction for efficacy and safety of heparin removal in a sheep model. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. The device, referred to as a vortex flow plasmapheretic reactor, consisted of two concentric cylinders, a priming volume of 45 ml, a microporous membrane for plasma separation, and an outer compartment where the immobilized heparinase I was fluidized separately from the blood cells. Manual white cell and platelet counts, hematocrit, total protein, and fibrinogen assays were performed. Heparin levels were indirectly measured via whole-blood recalcification times (WBRTs). The vortex flow plasmapheretic reactor maintained significantly higher heparin levels in the extracorporeal circuit than in the sheep (device inlet WBRTs were 1.5 times the device outlet WBRTs) with no hemolysis. The reactor treatment did not effect any physiologically significant changes in complete blood cell counts, platelets, and protein levels for up to 2 hr of operation. Furthermore, gross necropsy and histopathology did not show any significant abnormalities in the kidney, liver, heart, brain, and spleen.

This manuscript is an effort on behalf of the American Society of Pediatric Nephrology to provide recommendations designed to optimize the clinical care of pediatric patients with end-stage renal disease (ESRD). Although many of the recommendations are evidenced-based with the supporting data being derived from a variety of sources, including patient registries, others are opinion-based and derived from the combined clinical experience of the authors. In all cases, it is recommended that the decision to initiate dialysis should be made only after an assessment of a combination of biochemical and clinical characteristics. Irrespective of the choice of dialysis modality (hemodialysis v peritoneal dialysis), dialysis efficacy should be measured regularly, and the dialysis prescription should be designed to achieve target clearances. Attention to dialysis adequacy, control of osteodystrophy, nutrition, and correction of anemia is mandatory, because all may influence patient outcome in terms of growth, cognitive development, and school performance. Finally, the availability of a multidisciplinary team of pediatric specialists is desirable to provide all facets of pediatric ESRD care, including renal transplantation, in an optimal manner. Future clinical research efforts intended to address topics such as dialysis adequacy, anemia management, and growth should be encouraged.

Background. A novel plan of renal allograft allocation has been conducted by United Network for Organ Sharing Region 1 transplant centers since September 3, 1996, based upon HLA matching, time waiting, and population distance points. The objectives of this plan were to achieve a balance between increasing the opportunity of renal transplantation for those patients listed with long waiting times and promoting local organ donor availability. Methods. A single list of candidates was formulated for each cadaver donor, assigning a maximum of 8 points for time waiting, a maximum of 8 points for population distance from the donor hospital, and HLA points based upon the degree of B/DR mismatch. Additional points were awarded to a cross-match-negative patient with a panel-reactive antibody of >80%, and to pediatric patients. Results. The total number of kidneys transplanted to patients who had waited >3 years was 100 (46%), and to patients who had waited >2.5-3 years was 29 (13%). However, the total number of kidneys transplanted to patients with the maximum population distance points was only 72 (33%). Thus, although the plan achieved a favorable distribution of kidneys to patients with longer waiting times (nearly 60%), the other, equally important objective of promoting local donor availability was not initially accomplished. Moreover, minor HLA B/DR differences between the donor and the recipient (i.e., not phenotypically matched) were unexpectedly consequential in determining allocation. As a result of these observations, the following adjustments were made in the plan (as of December 3, 1997): a maximum of 10 points for population distance, a maximum of 8 points for time waiting (both by a linear correlation), and the retention of HLA points for 0 B/DR mismatch only. After these interval changes, the percentage of patients receiving a kidney with some population distance points increased from 85% to 96%. Conclusions. We have shown that a heterogeneous region of multiple transplant centers can devise (and modify) an innovative and balanced plan that provides an equitable system of allocation for an everincreasing number of patients.

Background. We have shown previously that heightened expression of the cytotoxic lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. Methods. We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. Results. Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. Conclusion. Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection. Despite the growing array of immunosuppressive therapies available to transplant recipients, acute allograft rejection is a common event and is a major factor in determining both short-term and long-term outcomes for the transplant recipient (1). The occurrence of acute rejection is a significant risk factor for hastened development of chronic rejection (2), and therefore prompt diagnosis and treatment of acute rejection episodes is of utmost importance. Currently, acute renal allograft rejection is suspected only when the serum creatinine level rises, after the adverse effect of immunological and inflammatory processes on graft function. Surveillance allograft biopsies may prove to be beneficial in predicting rejection, but clinical application is limited by the invasive nature of this procedure. The early phases of T cell activation and the early immune activation events that precede fixed graft tissue injury can now be detected by quantitative reverse transcription-polymerase chain reaction (RT-PCR*) in preclinical models (3). Using human renal allograft biopsy specimens, we have shown previously that quantitative RT-PCR analysis of intragraft gene expression of the cytotoxic cell (CL) effector molecules perforin (P), granzyme B (GB), and Fas ligand (FasL) correlates with the pathological diagnosis with extraordinary sensitivity and specificity, particularly when any two of the three genes are simultaneously up-regulated (4). In this study, we are testing the hypotheses that cytotoxic lymphocyte (CL) effector genes are coordinately expressed in peripheral blood leukocytes (PBLs) and renal allografts and CL effector molecule gene expression in PBLs correlates with the histological diagnosis.

Background Interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15, all T-cell growth factors (TCGFs), utilize the common IL-2 receptor gammac chain as a critical signaling component in their receptor complexes. We have bred IL-2-/- and IL-4-/- double knockout (DKO) mice and showed vigorous islet allograft rejection by DKO hosts. The identity of TCGFs that support the IL-2- and IL-4-independent allograft rejection is unclear. Methods We analyzed IL-9 gene expression in rejecting islet allografts in wild-type and in DKO mice, as well as in human renal transplant biopsy specimens, by reverse transcriptase polymerase chain reaction and compared the expression of IL-9 with that of other TCGFs. Results IL-9 gene expression was not detected in rejecting murine islet allografts in either wild-type or DKO recipient mice despite robust expression of other TCGFs, including IL-7 and IL-15. IL-9 transcripts were also not expressed in any of the human renal transplant biopsies obtained 4 to 251 days after transplantation, regardless of the presence or absence of histological evidence of rejection. Despite expression of IL-9 by DKO splenic cells upon in vitro mitogenic stimulation, IL-9 alone was unable to stimulate the proliferation of concanavalin A-activated splenic leukocytes harvested from DKO mice. Conclusion IL-9 is conspicuously absent despite vigorous expression of IL-2, IL-4, IL-7, and IL-15 genes during acute allograft rejection.

Background The interaction between CD40 and its ligand CD40L is essential for the development and maintenance of vigorous immunity. We have sought to determine: (i) whether a heightened level of CD40L transcripts is evident during acute allograft rejection and (ii) the kinetics of CD40L gene expression during allograft rejection. Methods. By using quantitative reverse transcriptase-assisted polymerase chain reaction techniques, we found that heightened CD40L gene expression is a correlate of acute human renal allograft rejection (P

Background. It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the indirect pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans. Methods. A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1 * 0101, DRB1 * 1501, and DRB1 * 0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [ 3 H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. Results. Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P

Background. Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. Methods. Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. Results. Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P