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Retransplantation accounts for approximately 15 % of the annual transplants performed in the USA, and in the recent International Collaborative Transplant Study report on pediatric patients 15.2 % of the 9209 patients included in the report were retransplant recipients. Although the significant advances in clinical management and newer immunosuppressive agents have had a significant impact on improving short-term allograft function, it is apparent that long-term allograft function remains suboptimal. Therefore, it is likely that the majority of pediatric renal allograft recipients will require one or more retransplants during their lifetime. Unfortunately, a second or subsequent graft in pediatric recipients has inferior long-term graft survival rates compared to initial grafts, with decreasing rates with each subsequent graft. Multiple issues influence the outcome of retransplantation, with the most significant being the cause of the prior transplant failure. Non-adherence-associated graft loss poses unresolved ethical issues that may impact access to retransplantation. Graft nephrectomy prior to retransplantation may benefit selected patients, but the impact of an in situ failed graft on the development of panel-reactive antibodies remains to be definitively determined. It is important that these and other factors discussed in this review be taken into consideration during the counseling of families on the optimal approach for their child who requires a retransplant.

Immunotolerance, which is nonimmunologic reactivity to specific tissue, was demonstrated in animals in the 1950s. However, despite assiduous efforts, it has not been reproduced in human solid-organ transplant to date. Fortuitously, clinical operational tolerance, which is stable graft function for > 1 year with no immunosuppression, has been demonstrated, primarily in a few nonadherent recipients of kidney and liver transplant. Vigorous efforts to identify a biomarker to distinguish recipients with clinical operational tolerance from nontolerant recipients have so far not been successful. However, weaning of immunosuppression in stable pediatric and adult liver transplant recipients has been successful in 60% and 20% of recipients. In kidney transplant recipients, clinical operational tolerance has been induced by combined kidney and hematopoietic cell transplant to induce chimerism and subsequent weaning of immunosuppression. Recently, the ex vivo expansion of autologous regulatory T cells with subsequent infusion has facilitated weaning of immuno suppression in liver transplant recipients. Protocols have been initiated to expand the use of regulatory T cells to kidney transplant recipients. These new methodologies have the potential to induce clinical operational tolerance in all recipients of a solid-organ transplant in the future, thus avoiding the long-term consequences of continued dependence on immunosuppressive medications for stable graft function.

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate post-transplant outcomes for patients treated with human growth hormone (rhGH) during the course of chronic renal insufficiency (CRI)., Study Design: Patients (the "cohort" group) were identified who had been enrolled in 2 controlled studies to determine the efficacy and safety of rhGH in growth-retarded children with CRI and were subsequently enrolled in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and received a renal transplant. Patient survival, graft survival, time to first acute rejection episode, causes of graft failure, adverse events, and serial growth data from transplant to 60 months were evaluated. Data from the cohort group of 102 patients were compared with data from 4913 primary transplants from "other NAPRTCS" recipients (the "control" group)., Results: No significant difference was seen in patient survival or graft survival, incidence of acute rejection episode, or time to first rejection episode between the cohort and control groups. No specific adverse events were attributable to previous rhGH treatment. Only 2 patients had post-transplant lymphoproliferative disease in the cohort group, with no other malignancies reported. The mean height z scores in the cohort group at baseline and 60 months after transplant were -1.92 and -1.90, and the Deltaz score at 60 months was +0.20 compared with the control group (-1.88 and -2.10)., Conclusions: Treatment of growth-retarded patients with CRI does not adversely affect graft function after renal transplantation. "Catch-down" growth does not occur after renal transplantation.

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.

Acute rejection is a frequent event in pediatric transplantation. In addition to graft loss, acute rejection episodes stimulate the development of chronic rejection and inhibit growth in children post-transplantation. In this study, we analyzed our data from 1987 through 1996 to identify acute rejection episodes in children. In 2,520 living donor (LD) transplants there were 2,540 rejection episodes (rejection ratio: 1.1), and in 2,579 cadaver donor (CD) transplants 3,653 episodes were observed (rejection ratio: 1.32). For LD recipients the first rejection occurred sooner when there was at least one HLA-DR mismatch (RR=1.6, p<0.001) and prophylactic T-cell antibody was not used (RR=1.4, p<0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p<0.001) and donor age below five years were risk factors (RR=1.5, p<0.001). Late initial acute rejections were seen in 327 of 1,471 patients (22.2%) who were rejection free at one year. At risk for the development of late rejections were children over the age of six years at transplantation (RR=1.7, p<0.001) and children of non-white origin (RR=1.5, p <0.002). For LD transplant recipients in the age range of 0-5 years, irreversible rejection was observed in 8.7% compared to 4.1% for older children (RR=1.46, p<0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p<0.00). The high frequency of rejection episodes in children and the greater irreversibility in younger children suggest pediatric patients may have a more robust immune response. Current ongoing studies in the molecular mechanisms of the pathogenesis of rejection in surveillance biopsies of children may help determine if this hypothesis is valid.

It is claimed that antibodies to the vascular-endothelial (VEM) antigen system are responsible for early renal transplant rejection. To evaluate the significance of these anti-VEM antibodies, we performed a retrospective study in 16 patients aged 14.8 +/- 5 (SD) years, who received either a living-related HLA-identical (n = 5) or haplo-identical (n = 11) transplant between 4/79 and 3/84. All patients had been transfused prior to transplantation. Lymphocyte and monocyte complement dependent cytotoxic crossmatches were performed using pre- and posttransplant recipients' sera and donor lymphocytes and monocytes. Lymphocytes were isolated with Ficoll-Hypaque; monocytes by adherence to plastic Petri dishes. Of the 16 patients studied, only 1 had a positive pre- and posttransplant monocyte crossmatch. Crossmatches using recipients' T and B lymphocytes were uniformly negative, indicating the presence of anti-VEM antibodies in the absence of anti-HLA antibodies in this 1 patient. This patient rejected the transplant in the immediate posttransplant period. Of the remaining 15 patients, 4 lost their kidneys within 16 days posttransplant, whereas 11 have good graft function. We conclude that anti-VEM antibody occurs rarely pretransplant and is an unusual cause of immediate rejection in the living-related transplant situation. However, when anti-VEM antibody is identified, transplantation should be avoided because of the likelihood of immediate early rejection.

Previous reports on the generation and nephritogenic capacity of post-transplant circulating immune complexes (CICs) are conflicting. To assess the pathogenicity of CICs in acute rejection (AR), 784 CIC determinations were performed on 392 serum samples from 27 pediatric renal allograft recipients using the C1q-solid phase assay (C1q-SPA) and the Raji cell radioimmunoassay (Raji-RIA). Serum samples from transplant recipients not undergoing rejection episodes and from normal subjects served as controls. Of the 784 CIC determinations, 723 (92.3%) were negative in both assays. CICs were present at some point post-transplant in eight (19.6%) recipients. Correlation of CIC levels with allograft rejection was found in only two patients with CIC levels responding to antirejection therapy; however, statistical analysis of data by chi 2 analysis failed to reveal a significant correlation of CICs with AR episodes. Allograft histology in three recipients demonstrated characteristic signs of AR. Immunofluorescent studies did not reveal significant deposition of immunoglobulin or complement. Sucrose density gradient ultracentrifugation studies confirmed the immune complex nature of materials reactive with the CIC assays. There was no immunological evidence supporting antithymocyte globulin (ATG) as an immunogen in patients demonstrating CICs post-transplant. CICs do not appear to be an important mediator of AR. Statistical analysis of data using the chi 2 test failed to reveal a positive correlation of CIC levels with AR or ultimate allograft outcome.

The immunological events mediated by, and antigen specificity of, allograft-bound lymphocytes (ABLs) are poorly understood. To further define the role of antibody-mediated rejection, a rejected allograft from a patient with primary anti-TBM disease was sterilely minced and pressed through a microscreen. The ABLs were isolated by density gradient centrifugation. Using this technique, 8.5 X 10(6) ABLs were isolated. Then 1 X 10(6) washed ABLs/ml were suspended in RPMI 1640 with 20% fetal calf serum and cultured in microtiter plates with media only, or with pokeweed mitogen (PWM) (100 micrograms/culture). The cells were incubated for 7 days and supernatants were collected and assayed for total IgG and IgM by a solid-phase enzyme immunoassay (EIA) and reactivity with normal human kidney targets by indirect immunofluorescence (IF) and immunoperoxidase (IP) techniques. Total IgG production was 500 ng/ml for both spontaneous and PWM stimulated cells. No IgM production was detected. IF and IP studies demonstrated IgG-anti-TBM antibodies in the spontaneous supernatants only. IgG antibodies reactive with peritubular capillaries (anti-PTC) were also noted. IgG-anti-TBM anti-bodies and antibodies reactive with arterioles were subsequently demonstrated by direct immunofluorescence techniques in the rejected allograft. Analysis of serum samples obtained at the time of allograft rejection showed no IF or IP reactivity with the kidney targets. Subsequent analysis of anti-TBM production by the patient's peripheral blood mononuclear cells (PBMs) showed IgM-anti-TBM only. These studies suggest that the IgG-anti-TBM and IgG-anti-PTC antibodies reactive with the allograft resulted from in situ antibody production by ABLs; the role of anti-TBM antibodies in mediating the AR is unclear, but their presence suggests recurrence of the original disease in the allograft. Anti-PTC antibodies could be important in mediation of the vascular AR.

Both magnetic resonance imaging (MRI) and ultrasound (US) have been reported to be useful in differentiating between acute allograft rejection and other causes of graft dysfunction in renal transplantation. The aim of this study was to evaluate the comparative usefulness of these techniques in the assessment of patients with acutely rising serum creatinine levels. Seventeen patients with 19 episodes of acute serum creatinine elevations were evaluated for the presence of acute rejection. The ultimate diagnoses of acute rejection were based on either renal pathological findings, or the response to standard antirejection therapy. Clinical, US and MRI diagnoses were assessed independently, without knowledge of the results of the other evaluation techniques. We found that US alone was useful in diagnosing acute rejection (x2 = 4.95, P less than 0.05), and when taken in the clinical setting was an added advantage (x2 = 6.68, P less than 0.01). MRI did not increase the diagnostic accuracy significantly.

Previous reports on the nephritogenic and immunological enhancing capacity of posttransplant circulating immune complexes (CICs) are conflicting and have been confined to the study of acute rejection episode (AR). This study was undertaken to assess the nephritogenicity of CICs in patients undergoing accelerated acute rejection (AAR) and chronic rejection (CR) episodes. We also assessed the possible role of CICs as mediators of immunological enhancement by assessing CIC levels in long-term-stable allograft recipients. To asses the nephritiogenic role of CICs, 98 CIC determinations were performed on 49 serum samples from 41 pediatric renal transplant recipients using the C1q solid-phase assay (C1q-SPA) and the Raji cell radioimmunoassay (Raji-RIA). Serum samples from normal subjects served as controls. No recipient undergoing AAR had evidence of CICs by eigher assay. 5 of 21 (23.8%) recipients undergoing CR had positive CIC levels in the Raji-RIA, while 4 of 21 (19%) recipients had positive CICs inthe C1q-SPA. There was no statistically significant correlation of CIC levels with long-term allograft function. In addition, there was no evidence supporting antithymocyte globulin as an immunogen in patients demonstrating posttransplant CICs. In summary, CICs do not appear to be an important mediator of AAR or CR episodes, and CICs were not routinely detected in patients with good long-term allograft function.

Several immunologic tests hve been developed to predict allograft rejection prior to functional renal impairment. Unfortunately, no test has as yet proven unequivocally to be of clinical value. Serial serum creatinine determinations and 131I hippuran scintiphotography have proven to be the most useful tests in detecting rejection episodes. Treatment of an acute rejection episode is often successful, but chronic rejection causes a slowly progressive deterioration of allograft function and is unresponsive to treatment.

To determine the possible role of the B lymphocyte alloantigen system in renal-transplant rejection, we examined serum specimens from 81 allograft recipients for cytotoxic activity against a panel of normal B lymphocytes. Specimens from 22 of 25 recipients undergoing allograft rejection demonstrated strong B-lymphocyte cytotoxicity whereas only 13 of 56 recipients with normal allograft function showed similar B lymphocyte cytotoxocitiy (P less than 0.0001). In the serum samples of recipients with graft rejection who were followed sequentially, B-lymphocyte cytotoxicity preceded or was concurrent with the onset of functional impairment. The results show that anti-B-lymphocyte antibodies are associated with rejection, but it is quite possible that they are the products of rejection rather than the cause.

Focal segmental and/or global sclerotic glomerular lesions with hyalinosis were noted in three allografts in association with the nephrotic syndrome (NS) and chronic rejection (CR). Similar lesions were absent in eight allografts with CR without NS. Previous reports have stressed the presence of this lesion in allografts with recurrence of the disease entity "idiopathic nephrotic syndrome with focal glomerulosclerosis". Both clinical and pathologic evidence suggest that recurrence was not a factor in the pathogenesis of the lesion in the three allografts with CR and NS. The presence of these lesions in failing allografts may represent the result of CR with associated NS rather than recurrence of the disease entity.